7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents

ABSTRACT

7-Azabicyclo[2.2.1]-heptane and -heptene derivatives with analgesic or anti-inflammatory activity are disclosed that can be administered to a mammal, including a human, to treat pain and inflammatory disorders. A method for the treatment of pain or inflammatory disorders is also presented that includes administering an effective amount of the compound or its pharmaceutically acceptable salt or derivative, or mixtures thereof, to a host in need of analgesic anti-inflammatory therapy, optionally in a pharmaceutically acceptable carrier or diluent.

This invention is in the area of 7-azabicyclo[2.2.1]heptane and -heptenederivatives and their method of manufacture and pharmaceutical use.

BACKGROUND OF THE INVENTION

Opiates, and in particular, morphine, are routinely administered for thetreatment of moderate to severe pain. Agents that are less potent thanmorphine, such as codeine, mixed agonist-antagonist opioids, andnon-opiate analgesics, including non-steroidal anti-inflammatory drugs(NSAIDS) are often used to relieve mild to moderate pain. Because of thewell-known side effects of opiates, including chemical dependence andrespiratory depression, there is a strong need for a non-opiate basedanalgesic for moderate to severe pain that would equal or exceed thepotency of opiate analgesics, yet lack the serious side effectsassociated with the administration of opiates. Spande, et al., reportedin 1992 that a potent nonopiate analgesic had been isolated from theskins of the Ecuadoran poison frog, Epipedobates tricolor. Spande, etal., 1992 J. Am. Chem. Soc., 114, 3475-3478. The structure of thecompound was determined by mass spectroscopy, infrared spectroscopy, andnuclear magnetic resonance asexo-2-(2-chloro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (see FIG. 1). Thecompound, which was named epibatidine, is the first member of the classof 7-azabicyclo[2.2.1]heptane compounds to be found in nature. Limitedpharmacological evaluation of epibatidine indicated that it isapproximately 500 times more potent than morphine in eliciting theStraub-tail response, and that this effect is not reversed by the opiateantagonist naloxone. In the hot plate analgesia assay, epibatidine isapproximately 200 times as potent as morphine. It has also beendetermined that epibatidine has a negligible affinity for opiatereceptors (1/8000 times that of morphine). Based on this data, itappears that epibatidine is a very potent analgesic that acts via anon-opiate mechanism. Since epibatidine was isolated from the skins ofthe Ecuadoran poison frog, its identification and characterization wasnot based on the synthesis of the compound. In fact, compounds in thefamily of 7-azabicyclo[2.2.1]-heptanes and -heptenes (also referred toas 7-azanorbornanes and 7-azanorbornenes, respectively) havehistorically been difficult to synthesize.

A possible entry into the 7-azabicyclo[2.2.1]-heptane and -heptene ringsystems involves the construction of the bicyclic ring through the 2+4cycloaddition of appropriately substituted 3-vinyl pyridine and pyrrolefragments, as indicated below. ##STR1## Unfortunately, pyrrole and itsderivatives readily undergo substitution reactions upon treatment withdienophiles (Diels, O. and Alder, K., Ann. 1932 498, 1.), with only afew exceptions reported (Wittig, G., Angew Chem. 1957 69, 245). Thepartial aromatic character of pyrrole limits its reactivity as a dieneand Michael-type addition products usually dominate. (Jones, R. A., TheChemistry of Heterocyclic Compounds, v.48 Pyrroles Wiley & Sons: NewYork. 1990.) Rate and yield enhancement of the Diels-Alder reactionbetween pyrroles and olefins have been obtained using Lewis acids(Donnini, G. P.; Just, G. J. Heterocycl. Chem. 1977, 14, 1423; Bansal,R. C.; McCulloch, A. W.; McInnes, A. G. Can. J. Chem. 1969, 47, 2391),and high pressures (Kotsuki, H.; Mori, Y; Nishizawa, H.; Masamitsu, O.;Matsuoka, K. Heterocycles, 1982, 19, 1915; Drew, M. G. B.; George, A.V.; Isaacs, is N. S.; Rzepa, H. S. T. C. S. Perkin Trans 1, 1985, 1277),but thus far these approaches have been limited in scope. The limitationin these reactions can often be traced to the inherent instability ofthe 7-azabicyclo[2-2.1]hept-2-ene products with respect to eitherretro-cycloaddition or retro-Mannich and re-aromatization pathways. Thisis especially true for cases where the resulting olefin isfunctionalized by electron-withdrawing groups. (Altenbach, H. J.;constant, D.; Martin, H. D.; Mayer, B.; Muller, M.; Vogel, E. Chem. Ber.1991, 124, 791.) An alternative method for the synthesis of the7-azanorbornane system was reported by Fraser, et al. (Can. J. Chem.1970, 48, 2065) but the long synthetic route and drastic reactionconditions involved are unsuitable for the synthesis of epibatidine. Fora review of 7-azanorbornene chemistry see: Kricka, L. J.; Vernon, J. M.Adv. in Heterocycl. Chem. 1974, 16, 87.

N-Carboalkoxypyrrole has been used in Diels-Alder reactions with severalacetylenic dienophiles to prepare norbornane derivatives. None of thesereported schemes, however, place an aromatic or heteroaromatic group inthe important is 2-position of the heptane or heptene ring. (Altenbach,H-J., et al., Chem. Ber. 1991, 124, 791; Altenbach, H-J., et al., Angew.Chem. Int. Ed. Engl. 1992 21(10), 778; Gabel, N. W., J. Org. Chem. 1962,27, 301; Toube, T. P. (1992) in: Pyrroles, Part 2 (Jones, R. A., ed.)John Wiley, New York. pp 92-95.)

In light of the analgesic potency of epibatidine as well as the strongneed for new potent, non-opiate analgesics, it would be useful toprovide methods for the synthesis of 7-azabicyclo[2.2.1]-heptane and-heptene derivatives that have pharmacological activity, and inparticular, analgesic activity, or that can be derivatized to compoundswith pharmacological activity.

Therefore, it is an object of the present invention to provide new7-azabicyclo[2.2.1]-heptane and -heptene derivatives with analgesicactivity.

It is another object of the present invention to provide methods for thesynthesis of 7-azabicyclo[2.2.1]-heptane and -heptene derivatives withanalgesic activity.

It is still another object of the present invention to provide newmethods for the treatment of pain.

SUMMARY OF THE INVENTION

7-Azabicyclo[2.2.1]-heptane and -heptene compounds are disclosed ofFormula (I): ##STR2## wherein:

R¹ and R⁴ are independently hydrogen, alkyl, including CH₃ ;alkylhydroxy, including CH₂ OH; alkyloxyalkyl, including --CH₂ OCH₃ ;alkylthioalkyl, including --CH₂ SCH₃ ; alkylamino, including --CH₂ NH₂ ;alkylaminoalkyl or alkylaminodialkyl, including CH₂ NH(CH₃) and CH₂N(CH₃)₂ ; oxyalkyl, including --OCH₃ ; carboalkoxy, includingcarbomethoxy; allyl, aryl and thioalkyl, including --SCH₃ ;

R³, R⁵ and R⁶ are independently hydrogen, alkyl, including --CH₃ ;alkylhydroxy, including --CH₂ OH; alkyloxyalkyl, including --CH₂ OCH₃ ;alkylthioalkyl, including --CH₂ SCH₃ ; alkylamino, including --CH₂ NH₂ ;alkylaminoalkyl or alkylaminodialkyl, including CH₂ NH(CH₃) and CH₂N(CH₃)₂ ; oxyalkyl, including -OCH₃ ; thioalkyl, including --SCH₃ ;halo, including Cl, F; haloalkyl, including CF₃ ; NH₂, alkylamino ordialkylamino, including --N(CH₃)₂ and --NHCH₃ ; cyclic dialkylamino,including ##STR3## amidine, cyclic amidine including ##STR4## and theirN-alkyl derivatives; ##STR5## --CO₂ H; CO₂ alkyl, including --CO₂ CH₃ ;--C(O)alkyl, including --C(O)CH₃ ; --CN, --C(O)NH₂, --C(O)NH(alkyl),--C(O)N(alkyl)₂, including --C(O)N(CH₃)₂ ; allyl, --SO₂ (alkyl), --SO₂aryl, including --SO₂ (C₆ H₅), --S(O)alkyl, --S(O)aryl, aryl,heteroaryl;

or ##STR6##

R₅ and R₆ together can be alkylidene or haloalkylidene, including --CH₂-- and --CF₂ --; epoxide (--O--); episulfide (--S--); imino(--N(alkyl)-- or --N(H)--) or a fused aryl or heteroaryl ring includinga fused phenyl ring;

R₂ is independently hydrogen, alkyl, including CH₃ ; alkenyl including--CH₂ --HC═CH₂ ; alkylhydroxy, including --CH₂ --OH; alkyloxyalkylincluding --CH₂ --O--(alkyl), alkylamine, including --CH₂ NH₂ ;carboxylate, C(O)Oalkyl, including CO₂ Me; C(O)Oaryl, C(O)Oheteroaryl,COOaralkyl, --CN, Q, C(O)Q, -alkyl(Q), -alkenyl(Q), -alkynyl(Q),--O--(Q) --S--Q, --NH--Q or --N(alkyl)--Q;

R₂ and R₃ together can be --C(O)--NR⁸)--C(O) or CH(OH)--N(R⁸)--C(O)--wherein R⁸ can be alkyl, aryl including phenyl, or heteroaryl;

R₇ is hydrogen, alkyl, including CH₃, or CH₂ CH₃ ; alkyl substitutedwith one or more halogens, including CH₂ CH₂ Cl; --CH₂ --(cycloalkyl),including --CH₂ --(cyclopropyl); --CH₂ CH═CH₂, --CH₂ CH₂ (C₆ H₅),alkylhydroxy, including CH₂ CH₂ OH, alkylamino(alkyl)₂, including CH₂CH₂ N(CH₃)₂ alkyloxyalkyl, alkylthioalkyl, aryl, dialkyl to form aquarternary ammonium including ##STR7##

wherein R⁹ is hydrogen or alkyl;

wherein Y' is CN, NO₂, alkyl, OH, --O-alkyl;

wherein Z is O or S;

wherein R¹⁰ and R¹¹ are each independently --O⁻, --OH, --O-alkyl,--O-aryl, --NH₂, --NH(alkyl), --N(alkyl)₂, --NH(aryl) and --N(aryl)₂ ;

Q is ##STR8## and wherein the Q moiety can be optionally substitutedwith 1 to 3 W substituents; and

W is alkyl, including CH₃ ; halo, including Cl and F; aryl, heteroaryl,OH, oxyalkyl, including --OCH₃ ; SH, thioalkyl, including --SCH₃ ;--SO(alkyl) including --SOCH₃ ; --SO₂ alkyl, including --SO₂ CH₃ ;--OCH₂ CH═CH₂, --OCH₂ (C₆ H₅), CF₃, CN, alkylenedioxy, including-methylenedioxy-; --CO₂ H, --CO₂ alkyl, including --CO₂ CH₃ ; --OCH₂ CH₂OH, --NO₂, --NH₂, --NH(alkyl), including --NHCH₃ ; --N(alkyl)₂,including --N(CH₃)₂ ; --NHC(O)alkyl, including --NHC(O)CH₃ ; --SO₂ CF₃,or --NHCH₂ aryl, including --NHCH₂ (C₆ H₅); and wherein

the - - - indicates an optional double bond.

These compounds have central and peripheral analgesic activity, and, oralternatively, anti-inflammatory activity, and thus can be administeredto a mammal, including a human, to treat pain and inflammatorydisorders. A method for the treatment of pain is also presented thatincludes administering an effective amount of the compound or itspharmaceutically acceptable salt or derivative, or mixtures thereof, toa host in need of analgesic therapy, optionally in a pharmaceuticallyacceptable carrier or diluent.

Facile processes for the preparation of the disclosed7-azabicyclo[2.2.1]-heptane and -heptene derivatives are also provided.In one embodiment, the pharmaceutically active compounds, or theirprecursors, are prepared by the cycloaddition reaction ofpentaammineosmium(II) complexes of pyrroles with dipolarophiles,including 3-vinyl pyridine derivatives. In another embodiment,pharmaceutically active compounds or their precursors, are prepared bythe Diels-Alder reaction of an N-(electronwithdrawing-substituted)pyrrole with an arylsulfonyl(optionallysubstituted aryl, alkyl, heterocyclic or heteroaryl)acetylene.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an illustration of the chemical structure ofexo-2-(2-chloro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (epibatidine).

FIGS. 2a and 2b are schematic illustrations of processes for thepreparation of active compounds through the Diels-Alder reaction of anN-(electron withdrawing substituted)pyrrole with anarylsulfonyl(optionally substituted aryl or heterocyclic)acetylene.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The term alkyl, as used herein, refers to a saturated straight,branched, or cyclic (or a combination thereof) hydrocarbon of C₁ to C₁₀,and specifically includes methyl, ethyl, propyl, isopropyl,cyclopropylmethyl, cyclobutylmethyl, butyl, isobutyl, t-butyl, pentyl,cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, heptyl, octyl,nonyl, and decyl.

The term lower alkyl, as used herein, refers to a C₁ to C₆ saturatedstraight, branched, or cyclic (in the case of C₅₋₆) hydrocarbon, andspecifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, cyclopropylmethyl, pentyl, cyclopentyl, cyclobutylmethyl,isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl,2,2-dimethylbutyl, and 2,3-dimethylbutyl.

The term alkylamino refers to an amino group that has an alkylsubstituent.

The term alkynyl, as referred to herein, refers to a C₂ to C₁₀ straightor branched hydrocarbon with at least one triple bond.

The term lower alkynyl, as referred to herein, refers to a C₂ to C₆alkynyl group, specifically including acetylenyl and propynyl.

The term aryl, as used herein, refers to phenyl, or substituted phenyl,wherein the substituent is halo, alkyl, alkoxy, alkylthio, haloalkyl,hydroxyalkyl, alkoxyalkyl, methylenedioxy, cyano, C(O)(lower alkyl),carboxy, CO₂ alkyl, amide, amino, alkylamino and dialkylamino, andwherein the aryl group can have up to 3 substituents.

The term halo, as used herein, includes fluoro, chloro, bromo, and iodo.

The term aralkyl refers to an aryl group with an alkyl substituent.

The term alkaryl refers to an alkyl group that has an aryl substituent,including benzyl, substituted benzyl, phenethyl or substitutedphenethyl, wherein the substituents are as defined for aryl groups.

The term heteroaryl or heteroaromatic, as used herein, refers to anaromatic moiety that includes at least one sulfur, oxygen, or nitrogenin the aromatic ring. Nonlimiting examples are furyl, pyridyl,pyrimidyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl,quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl,quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl,quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, and pyrazolopyrimidinyl.

The term organic or inorganic anion refers to an organic or inorganicmoiety that carries a negative charge and can be used as the negativeportion of a salt.

The term "pharmaceutically acceptable application" refers to an organicor inorganic moiety that carries a positive charge and that can beadministered in association with a pharmaceutical agent, for example, asa counteraction in a salt.

The term enantiomerically enriched composition or compound" refers to acomposition or compound that includes at least 95% by weight of a singleenantiomer of the compound.

The term pharmaceutically active derivative refers to any compound thatupon administration to the recipient, is capable of providing directlyor indirectly, the compounds disclosed herein.

As used herein, the term dipolarophile refers to a compound or moietythat reacts with a dipolar species to form a cycloaddition product.

As used herein, the term dienophile refers to a compound or moiety thatreacts with a diene to form a cycloaddition product.

As used herein, the term η refers to a pi-orbital complex of anunsaturated compound with a metal, and wherein the superscript after theη refers to the number of sp² carbon atoms bonded to the metal.

The term electron withdrawing substituent as used herein refers to asubstituent that pulls electron density from the moiety to which it isattached through induction or resonance. A wide variety of electronwithdrawing substituents are well known to those skilled in organicsynthesis.

II. Examples of Active Compounds

7-Azabicyclo[2.2.1]-heptane and -heptene derivatives of Formula (I) areprovided that have central and peripheral analgesic and, oralternatively, anti-inflammatory activity, and thus can be administeredto a mammal, including a human, to treat pain and inflammation. A methodfor the treatment of pain is also presented that includes administeringan effective amount of the compound or its pharmaceutically acceptablesalt or derivative, or mixtures thereof, to a host in need of analgesictherapy, optionally in a pharmaceutically acceptable carrier or diluent.

The numbering scheme for 7-azabicyclo [2.2.1]-heptane and -heptenederivatives is as illustrated below. ##STR9##

The 7-azabicyclo[2.2.1]-heptanes and -heptenes disclosed herein canexhibit a number of stereochemical configurations. As discussed above,the compounds are prepared in a Diels-Alder cycloaddition reaction of adienophile with a pyrrole, or a modification of the Diels Alder reactioninvolving the reaction of a dipolarophile with a pentaammineosmium(II)activated pyrrole. In the transition state of the cycloadditionreaction, there are two possible relative orientations of the diene ordienophile, referred to as endo and exo. Endo configurations are formedwhen other unsaturated groups in the dienophile (or dipolarophile) lienear the developing double bond in the diene. Exo configurations areformed when other unsaturated groups in the dienophile (ordipolarophile) lie away from the developing double bond in the diene.Depending on the substitution on the carbon atoms, the endo and exoorientations can yield different stereoisomers.

Carbon atoms 2, 3, 5 and 6 in 7-azabicyclo[2.2.1]heptanes and carbonatoms 2 and 3 or 5 and 6 in 7-azabicyclo[2.2.1]heptenes are chiral whenattached to different substituents. If at least one of the carbon in themolecule are chiral, the unsymmetrically substituted bicyclic compoundsexist as one or more diastereomeric pairs. The R groups in the activecompounds described herein can also include chiral carbons, and thus,optically active centers.

It is sometimes found that one or more enantiomers of a biologicallyactive compound is more active, and perhaps less toxic, than otherenantiomers of the same compound. Such enantiomerically enrichedcompounds are preferred for pharmaceutical administration to humans orother hosts.

One of ordinary skill in the art can easily separate the enantiomers ofthe disclosed compounds using conventional processes, and can evaluatethe biological activity of the isolated enantiomers using methodsdisclosed herein or otherwise known. Through the use of chiral NMR shiftreagents, polarimetry, or chiral HPLC, the optical enrichment of thecompound can be determined.

Classical methods of resolution include a variety of physical andchemical techniques. For example, since the compound has a basic amine(N⁷), it can be reacted with a chiral acid to form diastereomeric saltsthat may possess significantly different solubility properties.Nonlimiting examples of chiral acids include malic acid, mandelic acid,dibenzoyl tartaric acid, 3-bromocamphor-B-sulfonic acid,10-camphorsulfonic acid, and di-p-toluoyltartaric acid, and (-)-menthylchloroformate. Similarly, acylation of a free amine or hydroxyl group inthe molecule with a chiral acid also results in the formation of adiastereomeric amide or ester whose physical properties may differsufficiently to permit separation. Enantiomerically pure or enrichedcompounds can be also obtained by passing the racemic mixture through achromatographic column that has been designed for chiral separations,including cyclodextrin bonded columns marketed by Rainin Corporation.

The following are nonlimiting examples of specific compounds that fallwithin the scope of the invention. These examples are merely exemplary,and are not intended to limit the scope of the invention.

(A) Epibatidine isomers:

1-7-aza-2-exo-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane and itspharmaceutically acceptable salts, including the hydrochloride salt;1-7-aza-2-exo-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane and itspharmaceutically acceptable salts, including the hydrochloride salt;

d and 1-7-aza-endo-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane and itspharmaceutically acceptable salts, including the hydrochloride salts;

(B) d and l enantiomers of the 7-aza-bicyclo[2.2.1]heptane derivativescontaining the following substituents:

A combination of 7-methyl, 7-allyl-, 7-cyclopropylmethyl,7-cyclobutylmethyl, 7-phenethyl, 7-hydroxyethyl, 7-methoxyethyl,7-methylthioethyl, 7-dimethylaminopropyl, 7-formamidinyl,7-(2-chloroethyl), 7-disodium phosphate and 7-(4-methoxybenzyl)substituents with a 2-exo-(2-chloro-5-pyridyl) substituent;

2-exo-(3-pyridyl); 2-endo-(3-pyridyl); 7-methyl-2-exo-(3-pyridyl);7-cyclopropylmethyl-2-exo-(3-pyridyl); 7-phenethyl-2-exo-(3-pyridyl);

2-exo-(4-pyridyl); 7-methyl-2-exo-(4-pyridyl);7-allyl-2-exo-(4-pyridyl); 7-cyclopropylmethyl-2-exo-(4-pyridyl);

2-exo-(3-chloro-4-pyridyl);7-cyclopropylmethyl-2-exo-(3-chloro-4-pyridyl);7-phenethyl-2-exo-(3-chloro-4-pyridyl) 2-exo-(2chloro-3-pyridyl);2-exo-(2-chloro-4-pyridyl);

2-exo-(2-fluoro-5-pyridyl); 2-exo-(2-methoxy-5-pyridyl);2-exo-(2-methylthio-5-pyridyl); 2-exo-(2-methyl-5-pyridyl);2-exo-(2-dimethylamino-5-pyridyl); 2-exo-(2-hydroxy-5-pyridyl) and their7-cyclopropylmethyl derivatives;

The exo and endo isomers of: 2-phenyl; 2-(3-chlorophenyl);2-(3-dimethylaminophenyl); 2-(3-trifluoromethylphenyl);2-(3,4-methylenedioxyphenyl); 2-(3,4-dimethoxyphenyl);2-(4-fluorophenyl); 2-(4-hydroxyphenyl); 2-(4-methylthiophenyl);2-(4-methylsulfonylphenyl), 2-(3,5-difluorophenyl); 2-(2-chlorophenyl);2-(2-naphthyl); 2-(7-methoxy-2-naphthyl); 2-(5-chloro-2-thienyl);2-(chloro-5-thiazolyl); 2-(4-pyrimidyl); 2-(2-chloro-5-pyrimidyl);2-(5-chloro-2-pyridazinyl); 2-(1,2,5-thiadiazol-3-yl);2-(5-dimethylamino-2-furyl); 2-(5-indolyl); 2-(5-fluoro-3-indolyl);2-(5-methoxy-3-indolyl); 2-(4-chlorobenzyl);2-(5-chloro-3-pyridylmethyl); 2-(4-pyridylmethyl); 2-nicotinyl;2-(6-chloronicotinyl); 2-isonicotinyl; 2-(3-chloro-isonicotinyl);2(4-chlorobenzoyl); 2-(4-dimethylaminobenzoyl); 2-(3,4-dimethoxybenzoyl)and their 7-methyl, 7-cyclopropylmethyl, 7-allyl and 7-phenethylderivatives.

(C) The exo and endo isomers of7-aza-2-(2-chloro-5-pyridyl)-bicyclo[2.2.1]heptane containing thefollowing substituents at the 1, 2, 3, 4, 5 or 6 positions:

1 or 4-methyl; 1 or 4-hydroxymethyl; 1 or 4-methoxymethyl; 1 or4-carbomethoxy; 1 or 4-allyl; 1 or 4-benzyl; 1 or 4-(4-fluorobenzyl); 1or 4-(4-methoxybenzyl); 1,4-dimethyl; 1,4-bis(hydroxymethyl);1,4-bis(methoxymethyl); 1,6 or 4,5-butylidene;

Endo or exo-3-methyl; 3-hydroxymethyl; 3-methoxymethyl; 3-carbomethoxy;3-carboxy; 3-carbamyl; 3-cyano; 3-acetyl; 3-aminomethyl;3-dimethylaminomethyl; 3-methylthiomethyl; 3-phenylsulfonyl;3-methanesulfonyl; 3-benzyl; 3-allyl; 3-cyano-1,4-dimethyl;3-hydroxymethyl-1,4-dimethyl, 3-methoxymethyl-1,4-dimethyl;3-methylthiomethyl-1,4-dimethyl; 5,6-bis(trifluoromethyl); 5 or6-methoxy; 5 or 6-methyl; 5,6-dimethyl; 5,6-dicarbomethoxy;5,6-bis(hydroxymethyl); 5,6-bis(methoxymethyl); 5 or 6-chloro; 5 or6-hydroxy; 5,6-dehydro; 5,6-dehydro-1,4-dimethyl; 3,3-dimethyl;2-methyl; 2,3-dimethyl, 5,6-methylene;

and their corresponding 7-methyl, 7-cyclopropylmethyl, 7-allyl,7-phenethyl and 7-(4-fluorobenzyl) derivatives.

(D) 7-Aza-2-(2-chloro-5-pyridyl)-bicyclo[2.2.1]hept-2-ene and its7-methyl, 7-allyl, 7-cyclopropylmethyl, 7-phenethyl and7-(4-methoxyphenethyl) derivatives; and

the corresponding 1,4-dimethyl; 1 or 4-methyl; 5,6-dimethyl and5,6-bis(trifluoromethyl) analogs.

(E) Benzo[5a,6a]epibatidine and its N-methyl derivative;2,3-dehydroepibatidine; 5,6-bis(trifluoromethyl)deschloroepibatidine;2-carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptane;2-cyano-7-methyl-7-azabicyclo[2.2.1]heptane;trans-2,3-bis-carbomethoxy-7-azabicyclo[2.2.1]-heptane;exo-2-amino-7-methyl-7-azabicyclo[2.2.1]-heptane;exo-2-(1-pyrrolylmethyl)-7-methyl-7-azabicyclo [2.2.1]heptane;exo-2-hydroxymethyl-7-methyl-7-azabicyclo[2.2.1]heptane;exo-2-hydroxymethyl-7-methyl-2-azabicyclo[2.2.1]heptane.

III. Methods for the Synthesis of Optionally Substituted7-Azabicyclo[2.2.1]-heptanes and -heptenes A. SYNTHESIS OF THE7-AZABICYCLO[2.2.1]-HEPTANE OR -HEPTENE RING SYSTEM FROM PYRROLES VIAPENTAAMMINEOSMIUM(II) COMPLEXES

It has been discovered that 7-azabicyclo[2.2.1]-heptane and -heptenederivatives can be prepared by combining a dipolarophile with anoptionally substituted pyrrole that has been complexed withpentaammineosmium(II).

Any dipolarophile can be used in this reaction that reacts with thepentaammineosmium pyrrole complex to provide an optionally substituted7-azabicyclo[2.2.1]-heptene, which is easily converted to thecorresponding 7-azabicyclo[2.2.1]-heptane. Examples of dipolarophilesinclude compounds of the is structure Z₁ --C═C--Z₂, wherein Z₁ and Z₂are independently electron withdrawing groups, including withoutlimitation, esters, nitriles, ketones, aldehydes, amides, --NO₂,sulfones, anhydrides, --CF₃, pyridinium salts, and for example,CO(alkyl, aryl or heteroaryl), C(O)H, CO₂ (alkyl, aryl, or heteroaryl),SO₂ (alkyl, aryl, or heteroaryl), or wherein Z₁ and Z₂ are together(CO)₂ O, or (CO)₂ N. Specific compounds include N-methylated and6-carboxylated pyridyl acrylates, alkyl acrylate, alkyl methacrylate,pyridyl substituted vinyl sulfones, acrylonitriles, anhydrides,maleimides, alpha-methylene-δ-butyrolactone, maleates, and fumarates.

Analogously, any optionally substituted pyrrole can be used that oncomplexation with pentaammineosmium(II) will react with a dipolarophile.Examples of suitable pyrroles include 2,5-dialkylpyrrole,2-alkylpyrrole, 3-alkylpyrrole, 1-alkylpyrrole, 3,4-dialkylpyrrole,pyrrole, 1-silylated pyrrole, (1, 2, or 3)alkoxy or amino pyrrole,2,3-dialkoxypyrrole, 2,5-dialkoxypyrrole, and 3,4-dialkoxypyrrole.

As shown below in Scheme 1, a complex is readily formed between pyrroleand the π-base pentaammineosmium(II) in which the osmium coordinates theheterocycle across C2 and C3. At 20° C., this species is in equilibriumwith its linkage isomer in which the metal binds across C3 and C4.Although the 3,4-η species is only a minor component (▴G_(iso) >3kcal/mol), the metal coordination in this species renders the remainingportion of the pyrrole an azomethine ylide (R₂ C⁺ --N(R)--C--R₂ ←→R₂C═N⁺ (R)--C⁻ R₂), and thereby dramatically enhances the tendency of theligand to undergo a 1,3-dipolar cycloaddition with suitabledipolarophiles. ##STR10##

The resulting 7-azabicyclo[2.2.1]hept-5-ene ligand is unstable withrespect to cycloreversion, but metal coordination greatly stabilizes thecomplex and thus provides the opportunity to carry out functional grouptransformations while keeping the bicyclic framework intact. Forexample, derivatization of electron-withdrawing groups in the 2- or3-positions of the norbornene framework, using conventional processes,provides a wide array of functionalized 7-azanorbornenes. Specifically,as shown in Scheme 2 below, the exo-carbonyl cycloadduct complex 2,prepared in a one-pot synthesis from 2,5-dimethylpyrrole, is reduced tothe corresponding alcohol and oxidatively decomplexed to yield therelatively inaccessible 5-hydroxymethyl-7-azanorbornene 3. ##STR11##

This approach can be used to construct the epibatidine ring system if a3-vinyl pyridine is used as the dipolarophile. The use ofmethyl-trans-3-(3-pyridyl)-acrylate in the above reaction sequence(using the 2,5-dimethylpyrrole complex shown in Scheme 2), yieldscompound 4, shown below, which contains the carbon skeleton of thenatural product. ##STR12##

Epibatidine has no substitution at the bridgehead carbons (C¹ and C⁴).The reactivity of simple pentaammineosmium(II)- pyrrole complexes withdipolarophiles decreases in the order2,5-dimethylpyrrole >N-methylpyrrole>pyrrole. Generally, additionalactivation of the dipolarophile, by careful selection of the electronwithdrawing group attached to the olefin, or high pressure is requiredto obtain cycloadducts without substitution at the bridgehead positions.Although the parent pyrrole complex gives complex mixtures, the N-methylpyrrole reacts with the N-methylated and 6-carboxylated pyridylacrylates to yield cycloadducts 5 and 6 as single diastereomers.##STR13##

An alternative method for stabilization of the azabicyclo[2.2.1]heptanenucleus involves protonation of the secondary amine (and pyridyl group)followed by oxidative removal of the metal and in situ hydrogenation ofthe azanorbornene. An example of this method is shown in Scheme 3 belowfor the synthesis of the1,4-dimethyl-exo-carbomethoxy-norchloroepibatidine 7. ##STR14##

The process for preparing optionally substituted7-azabicyclo[2.2.1]heptanes and 7-azabicyclo[2.2.1]hept-5-enes viapentaammineosmium(II) complexes proceeds in three steps. In the firststep, the optionally substituted pyrrole is treated withpentaammineosmium(II). An excess of the pyrrole complex is usuallypreferred. Pentaammineosmium(II) is generated in situ by the reductionof pentaammineosmium(III) with a one electron reducing agent that has areducing potential of less than -0.75 volts versus hydrogen. Thecounteranion of pentaammineosmium (II) can be any anion that does notadversely affect the overall reaction. Typical counteranions are CF₃ SO₃⁻ (Otf⁻), PF₆, X⁻, and (alkyl or aryl)SO₃ ⁻.

Any chemical or electrochemical reducing agent that can reduce theosmium complex from a III valence state to a II valence state and whichdoes not cause or participate in undesired side reactions is suitable.Examples of appropriate reducing agents include magnesium, zinc,aluminum, sodium, cobaltocene and electrochemical reduction. In apreferred embodiment, activated magnesium powder is used.

The optionally substituted pyrrole, pentaammineosmium(III), and reducingagent are stirred at a temperature ranging between 0° C. and 50° C.until the desired organometallic complex is formed, typically between0.1 and 1.0 hours. The reaction can be carried out in a polar ornonpolar solvent, including but not limited to N,N-dimethylacetamide,N,N-dimethylformamide, water, methanol, acetonitrile, acetone,dimethylsulfoxide, CH₂ Cl₂, or dimethoxyethane. The reaction is carriedout in the absence of O₂, and typically under nitrogen, at a pressure of1 atm or greater.

In the second step of the process, the dipolarophile is added to thestirring solution of the pyrrole pentaammineosmium (II) complex toproduce an optionally substituted 7-azabicyclo[2.2.1]hept-5-ene. Anymolar ratio of dipolarophile to pyrrole can be used that provides thedesired results. Typically, a molar ratio of dipolarophile to pyrroleranging between approximately 1 and 10 provides a suitable yield ofproduct. The reaction solution is stirred at a temperature rangingbetween 10 and 50° C. until the product is formed, typically between 1and 24 hours.

In an optional step after the bicyclic ring system is formed, and whilepentaammineosmium is still complexed to the pi-orbital of the heptenemoiety, functional groups on the bicyclic ring can be derivatized usingconventional processes. For example, esters can be reduced to alcohols,nitrites to amines, sulfones to sulfides, nitro groups to amines, andamides to amines. Sulfones and carboxylates can be reductivelyeliminated using the Barton decarboxylation procedure. High temperaturesand strong bases should be avoided in the functionalization proceduresto avoid ring disruption and unwanted side reactions.

In the third step of the reaction, the pentaammineosmium (II) complex isremoved from the optionally substituted 7-azabicyclo[2.2.1]hept-5-eneby, for example, treatment with cerium (IV) or oxygen in acidicsolution. For example, the 7-azabicyclo[2.2.1]hept-5-ene can be treatedwith one equivalent of cerium reagent at 20° C. in a polar solvent suchas acetonitrile. Appropriate reagents include Ce(NO₃)₆ (NH₄)₂,DDQ, andother inorganic or organic oxidants with E>+0.70 volts versus hydrogen.Alternatively, the osmium reagent can be removed by heating the complexas necessary, usually between approximately 50° C. and 100° C.

Using the method of synthesis described above, a wide variety ofsubstituted 7-azanorbornanes and 7-azanorbornenes can be prepared.Examples of representative compounds are summarized in Tables 1 and 2.

Some of them are useful as intermediates for the synthesis of desiredcompounds containing complex heteroaryl or polar substituents as R₂and/or R₃.

                  TABLE 1                                                         ______________________________________                                          #STR15##                                                                       -            R.sub.1 R.sub.2    R.sub.3                                    ______________________________________                                        7-azabicyclo[2.2.1]heptane                                                                    H       exo-CH.sub.2 OH                                                                          H                                                H    exo-CH.sub.2 OH.sub.3  H                                                 H    exo-CH.sub.2 OH   endo-3-py                                              H    exo-CO.sub.2 CH.sub.3  endo-3-py                                         H    exo-CO.sub.2 CH.sub.3  exo-3-py                                          H    exo-SO.sub.2 Ph   endo-3-py                                              H    endo-SO.sub.2 Ph exo-3-py                                            7-azabicyclo[2.2.1]hept-5-ene    H    exo-CH.sub.2 OH   H                                     CBz  exo-CH.sub.2 OH   H                                                      Cbz  exo-OCBz   H                                                             H    exo-CH.sub.2 OH   endo-3-py                            ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                          #STR16##                                                                       Example R.sub.1 R.sub.2         R.sub.3                                    ______________________________________                                            15 CH.sub.3                                                                              exo-CCOMe         H                                              15          CH.sub.3     endo-COOMe                  H                        16          CH.sub.3     exo-C.tbd.N                    H                     16          CH.sub.3     endo-C.tbd.N                   H                     17          H       exo-COOMe                   endo-COOMe                    18          H       exo- --C(O)--N(Ph)--C(O)--                                18          H       endo- --C(O)--N(Ph)--C(O)--                               19          Et      exo- --C(O)--N(Ph)--C(O)--                                20          H       exo- --C(O)--N(Ph)--C(O)--                                21          CH.sub.3     exo-CH.sub.2 NH.sub.2                  H                                             22         CH.sub.3     exo- CH.sub.2                                        NC.sub.4 H.sub.4               H                                               23          CH.sub.3     exo-CH.sub.2                                        OH                   H                         24          CH.sub.3     exo-CH.sub.2 OOCPh                H                   -                                                                            25                                                                                                        ##STR17##                                       ______________________________________                                    

Methods for preparing compounds of Formula (I) via derivatization of a5,6-η² -7-aza-bicyclo[2.2.1]hept-5-ene are set out below. These examplesare merely illustrative, and are not intended to limit the scope of theinvention.

EXAMPLE 1 Preparation of1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene (8)

A solution of the 5,6-η² osmium complex of compound 8 (727 mg, 1.0 mmol)in 2 grams acetonitrile was protonated with excess triflic acid (250 mg,1.67 mmol) and treated at -10° C. with a likewise-cooled solution ofceric ammonium nitrate (560 mg, 1.02 mmol) and triflic acid (560 mg,3.73 mmol) in 2 grams acetonitrile. Water (1-2 ml) was added to dissolvethe precipitated salts, the mixture made basic with 40 ml 10% aqueoussodium carbonate and the product extracted with 5×20 ml methylenechloride. The extract was dried over MgSO₄ and the solvent evaporated,yielding 147 mg of brown oil. The crude product was purified by silicagel column chromatography using 1:10 of 15 wt % NH₃ inmethanol/methylene chloride, yielding 62 mg (41%) of pure 8. (oil, R_(f)=0.5). ¹ H NMR (300 MHz, CDCl₃) d 6.31 (d, J=5.3 Hz, 1H), 6.09 (d, J=5.3Hz, 1H), 3.99 (dd, J=10.3, 2.1 Hz, 1H), 3.67 (dd, J=10.3, 2.1, 1H),3.6-2.8 (v br, ˜2H, OH and NH), 1.4-1.8 (m, 3H), 1.48 (s, 3H), 1.47 (s,3H); ¹³ C NMR (75 MHz, CDCl₃) d 145.2 (CH), 141.5 (CH), 69.9 (C), 67.0(C), 61.5 (CH₂), 41.7 (CH), 37.0 (CH₂), 18.9 (CH₃), 15.7 (CH₃); Thismaterial was further characterized by conversion to the picrate salt.m.p. 186-188° C.; Anal. Calcd. for C₁₅ H₁₈ N₄ O₈ : C, 47.12; H, 4.75; N,14.65. Found: C, 46.96; H, 4.52; N, 14.66.

EXAMPLE 2 Preparation ofN-CBZ-1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene(9) andN,O-Bis-CBZ-1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene(10)

The crude aminoalcohol 8 obtained from 1.0 mmol of the osmium complex asdescribed above was suspended in a solution of aqueous Na₂ CO₃ (0.38grams in 2 grams water), and the mixture chilled to 0° C. Benzylchloroformate (510 mg, 3 mmol) was added, and the mixture allowed towarm to room temperature with vigorous stirring. After 20 hours at 25°C. the mixture was extracted with methylene chloride, and the extractsdried and rotoevaporated, yielding 0.4 grams of brown oil. The crudematerial was chromatographed twice using 1:8 ethyl acetate/petroleumether, yielding 43 mg (10%) of 9 and 64 mg (22%) of 10 (R_(f) =0.5 and0.1, respectively) For 9: ¹ H NMR(300 MHz, CDCl₃) d 7.32 (m, 5H,Phenyl), 6.06 (ABq, J=5.7 Hz, 2H, H5 and H6), 5.04 (s, 2H, OCH₂ Ph),3.69 (m, 2H, CH₂ OH), 2.18 (br s, 1H, OH), 1.75 (2×s, 6H, CH₃), 1.7 (m,overlap, 1H), 1.55 (m, 2H); ¹³ C NMR (75 MHz, CDCl₃) d 155.2 (CO), 140.5(CH, C5 or C6), 140.2 (CH, C6 or C5), 136.4 (C, ipso), 128.3 (CH), 127.9(CH), 127.8 (CH), 71.1 (C), 69.0 (C), 66.4 (CH₂ OH), 63.0 (CH₂), 45.6(CH), 37.7 (CH₂), 19.4 (CH₃), 16.8 (CH₃). For 10: ¹ H NMR(300 MHz,CDCl₃) d 7.37 (m, 5H, Phenyl), 7.32 (m, 5H, Phenyl), 6.07 (ABq, J=5.5Hz, 2H, H5 and H6), 5.16 (s, 2H, OCH₂ Ph), 5.05 (ABq, J=13.5 Hz,2H, OCH₂Ph), 4.33 (dd, J=10.5, 7 Hz, 1H, 1/2 CH₂ OCBZ), 4.06 (dd, J=10.5, 7.5Hz, 1H, 1/2CH₂ OCBZ) 1.94 (m, 1H, H2), 1.79 (s, 3H, CH₃) 1.75 (s, 3H,CH₃), 1.60 (dd, J=11.4, 9 Hz, 1H, H3_(endo)), 1.4 (dd, J=11.4, 3. 6 Hz,H3_(exo)) ¹³ C NMR (75 MHz, CDCl₃) d 155.0 (CO), 154.9 (CO), 140.5 (CH,C5 or C6), 140.5 (CH, C6 or C5), 136.4 (C, ipso), 135.2 (C, ipso), 128.5(overlap of 2×CH), 128.4 (CH), 128.3 (CH), 128.0 (CH), 127.8 (CH), 70.8(C), 69.6 (overlap of 2×CH₂), 68.9 (C), 66.3 (CH₂ O), 43.2 (CH, C5),38.7 (CH₂, C6), 19.3 (CH₃), 17.0 (CH₃).

EXAMPLE 3 Preparation of1,4-Dimethyl-2-endo-(3'-pyridyl)-3-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]hept-5-ene(11)

The corresponding 5,6-η² osmium complex was treated as described abovefor compound 8. Diagnostic ¹ H NMR information: 6.43 (d, J=6H, 1H, H5 orH6), 6.0 (d, J=6 Hz, 1H, H6 or H5), 4.0 (dd, J=10,2.5 Hz, 1H, 1/2 CH₂OH), 3.75 (dd, J=10, 2.5 Hz, 1/2 CH₂ OH), 1.55 (s, CH₃), 1.38 (s, CH₃).

EXAMPLE 4 Preparation of1,4-Dimethyl-2-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane (12)

A sample of crude compound 8 (85 mg, 0.56 mmol) was stirred with 30 mg10% Pd-on-C and 0.5 g methanol in a 5-ml round-bottomed flask under 1atmosphere of H₂ for 30 minutes. The reaction mixture was filteredthrough celite and evaporated, yielding 78 mg of oil. Purification bypreparative thin layer chromatography (0.25 mm, 20×20 cm; Eluent=1:6 15%NH₃ in MeOH, CH₂ Cl₂), yielded 14 mg (16%) of pure 12 (R_(f) =0.5) ¹ HNMR(300 MHz, CDCl₃) d 3.89 (br, 2H, NH and OH), 3.82 (d J=10.6 Hz, 1/2CH₂ OH), 3.38 (d, J=10.6 Hz, 1/2 CH₂ OH), 1.7-1.5 (m, 7H, 3×CH₂ +CH),1.41 (s, 3H, CH₃), 1.37 (s, 3H, CH₃); ¹³ C NMR (75 MHz, CDCl₃) d 66.8,64.0, 63.8, 45.5, 40.0, 39.1, 39.07, 20.6, 17.8

EXAMPLE 5 Preparation of1,4-Dimethyl-2-exo-carboxymethyl-7-azabicyclo[2.2.1]heptane (13)

The corresponding 2,3-η2-osmium complex 18 was protonated anddecomplexed with Ce(IV) as described for 8. The acetonitrile wasevaporated and the unstable, protonated 7-azanorbornene hydrogenated inmethanol as described for 12. Compound 13 was obtained as an oilfollowing an aqueous workup (e.g., see procedure for 8) and preparativethin layer chromatography purification. ¹ H NMR(300 MHz, CDCl₃) d 3.60(s, 3H, CH₃ O), 2.63 (dd, J=8.1, 5.1 Hz, 1H, H2), 2.49 (br s, 1H, NH),1.82 (dd, J=12.2, 8.1 Hz, 1H, H3_(endo)), 1.75-1.2 (m, overlap, 5H),1.32 (s, CH₃), 1.2 (s, 3H, CH₃); ¹³ C NMR (75 MHz, CDCl₃) d 176.5 (CO),67.7, 63.4, 53.0, 51.3, 44.0, 38.3, 36.7, 20.5, 18.3.

EXAMPLE 6 Preparation of1,4-Dimethyl-2-endo-(3'-pyridyl)-3-exo-carboxymethyl-7-azabicyclo[2.2.1]heptane(14a) and its exo-pyridyl-endo-carboxyl isomer (14b)

These isomers were obtained as an inseparable 94:6 mixture from thecorresponding mixture of osmium complexes following the procedure for13. For 14a, ¹ H NMR(300 MHz, CDCl₃) d 8.45 (m, 2H, H2' and H6'overlap), 7.49 (dt, J=7.8, 1.5 Hz, 1H, H4'), 7.23 (dd, J=7.8, 4.8 Hz,1H, H5'), 3.64 (s, 3H, CH₃ O), 3.29 (dd, J=5.9, 2.1 Hz, 1H, H2), 2.95(d, J=5.9 Hz, 1H, H3), 2.62 (br s, 1H, NH), 1.85-1.6 (m, 2H, CH₂ 's),1.5 (m, 1H), 1.35 (m, 1H), 1.29 (s, 3H, CH₃), 1.26 (s, 3H, CH₃); ¹³ CNMR (75 MHz, CDCl₃) d 175.7 (CO), 149.8 (CH), 148.2 (CH), 135.3 (CH),134.1 (C), 123.1 (CH), 67.6 (2×C overlap), 58.7 (CH), 58.3 (CH), 51.7(CH₃ O), 38.6 (CH₂), 30.3 (CH₂), 19.3 (CH₃), 18.7 (CH₃). Diagnosticfeatures of 14b: d 3.36 (d, J=6 Hz, H2), 2.8 (dd, J=6, 2 Hz, H3)

EXAMPLE 7 Preparation of1,4-Dimethyl-2-endo-(3'-pyridyl)-3-exo-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane(15)

Compound 14 was reduced with lithium aluminum hydride in ether, yieldinga clear resin after an aqueous workup. Diagnostic ¹ H NMR resonances:3.87 (dd, J=10.6, 2.8 Hz, 1H, 1/2 CH₂ OH), 3.46 (dd, J=10.6, 3.0 Hz, 1H,1/2 CH2OH), 3.16 (dd, J=5.0, 1.9 Hz, 1H, H2), 1.5 (s, 3H, CH₃), 1.25 (s,3H, CH₃)

EXAMPLE 8 Preparation of1,4-Dimethyl-2-endo-(3'-pyridyl)-3-exo-phenylsulfonyl-7-azabicyclo[2.2.1]heptane(16a) and its exo-pyridyl, endo-phenylsulfonyl isomer (16b)

The procedure for compounds 13 and 14 was followed yielding a mixture ofisomeric 7-azanorbornanes. Diagnostic ¹ H NMR peaks for major isomer:3.6 (d, J=7 Hz, 1H, CH_(endo)), 2.95 (dd, J=7, 1.5 Hz, 1H, CH_(exo)),1.85 (s, 3H, CH₃), 1.25 (s, 3H, CH₃)

EXAMPLE 9 Preparation of [Os(NH₃)₅ (2,3-η² -2,5-dimethylpyrrole)] (OTf)₂(17)

To a solution of [Os(NH₃)₅ OTf]OTf₂ (1.445 grams, 2.00 mmol) in 1.5grams N,N-dimethylacetamide was added 2,5-dimethylpyrrole (1.5 g, 16mmol) and activated Mg° (1.0 g, 41 mmol) and the slurry stirred for45-60 minutes. The slurry was filtered through a medium-porosity fritinto 150 ml CH₂ Cl₂, giving a light yellow precipitate, which wasfiltered, washed with CH₂ Cl₂ and ether, then dried. The yield of alight-yellow powder was 1.23-1.31 g (92-98%).

EXAMPLE 10 Preparation of 5,6-exo-η² -Os(NH₃)₅-1,4-dimethyl-2-exo-carbomethoxy-7-azabicyclo-[2.2.1]hept-5-ene) (OTf)₂(18)

The 2,5-dimethylpyrrole complex (669 mg, 1.0 mmol) was suspended in 2grams methyl acrylate and the slurry stirred for 1 hour. Acetonitrile(c. 1 ml) was added to dissolve the solids and the resulting solutionadded dropwise to 50 ml of ether while stirring. The precipitate wasfiltered, washed with ether and dried, yielding 730 mg (97%) of anoff-white powder. ¹ H NMR (300 MHz, CD₃ CN) d 3.97 (br s, 3H,trans-NH₃), 3.65 (s, 3H, CH₃ O), 3.34 (br s, 12H, cis-NH₃), 3.17 (d,J=6.3 Hz, 2H, H5 or H6), 3.13 (d, J=6.3 Hz, 1H, H6 or H5), 2.77 (dd,J=8.1, 4.2 Hz, 1H, H2), 2.14 (br s, 1H, NH), 2.05 (dd, J=11.6, 8.1 Hz,1H, H3_(endo)), 1.63 (dd J=11.6, 4.2 Hz, H3_(exo)), 1.39 (s, 3H, CH₃),1.24 (s, 3H, CH₃); ¹³ C NMR (75 MHz, CD₃ CN) d 176.4 (CO), 75.7 (C),71.0 (C), 59.1 (CH), 58.0 (CH), 55.3 (CH), 51.6 (OCH₃), 47.1 (CH₂), 18.3(CH₃), 15.9 (CH₃); Anal. Calcd. for C₁₂ H₃₀ N₆ O₈ S₂ F₆ Os: C, 19.10; H,4.01; N, 11.14. Found: C, 18.57; H, 3.96; N, 11.02.

EXAMPLE 11 Preparation of Pentaammineosmium-Pyrrole Complexes: 2,3-η²-[Os(NH₃)₅ ]-Ligand](OTf)₂, where Ligand is pyrrole or N-methyl pyrrole

A mixture of [Os(NH₃)₅ OTf](OTf₂) (723 mg, 1.0 mmol),N,N-dimethylacetamide (1 g), DME (3 g), pyrrole or N-methyl pyrrole (1g) and magnesium (0.5 g) was stirred for 1 hour. The solution wasfiltered through a 60-ml medium fritted glass funnel with the aid of10-15 ml of DME, and the filtrate added dropwise to methylene chloride(150 ml). The resulting precipitate was filtered, and washed withportions of methylene chloride (20 ml) and ether (2×20 ml), and driedunder nitrogen. The yield of this reaction is typically 90-95% of ayellow-orange solid containing approximately 8% of a binuclear impurity.

EXAMPLE 12 Preparation of Pentaammineosmium-Cycloadduct Complexes

The pentaammineosmium-pyrrole complex obtained from Example 11 wastreated with an excess (3-30 eq) of a dipolarophile in eitheracetonitrile or N,N-dimethylacetamide solution. After 1-10 hours, thesolution was added to ether or methylene chloride with stirring (20 mlof ether per gram of acetonitrile or 75 ml methylene chloride per gramof N,N-dimethylacetamide). The resulting precipitate was worked up asdescribed in Example 11 providing a yield of 85-95%.

EXAMPLE 13 One-Pot Process for the Synthesis ofPentaammineosmium-Cycloadduct Complexes

A dipolarophile (e.g., methyl acrylate) was added directly to thereaction mixture in the synthesis of the parent pyrrole complex asdescribed in Example 11. After a suitable reaction time (e.g., 1-10hours), the mixture was filtered to remove the magnesium, and thefiltrate was added to 1:1 methylene-chloride/ether (100 ml for everygram of N,N-dimethylacetamide used in the synthesis) with stirring. Thesolid was isolated as described in Example 11 yielding the cycloadductcomplex as mono-N,N-dimethylacetamide solvate in ˜95% yield.

EXAMPLE 14 One-Pot Process for the Synthesis of 7-Azanorbornanes fromthe Pentaammineosmium-Cycloadduct Complex

The cycloadduct complex (1.0 mmol) prepared in Example 13 was dissolvedin acetonitrile (4 g), protonated with triflic acid (3-5 eq), andtreated with DDQ (1 eq). The dark solution was transferred to a 50-mlround-bottomed flask with the aid of an additional 20 ml ofacetonitrile, treated with 10% palladium-on-carbon (approximately 0.5 g,40 mole %), and hydrogenated under 1 atm H₂ (balloon) for a suitableperiod of time (2-20 hours) (The pyrrole-derived complexes, lacking asubstituent on nitrogen, underwent reductive amination to N-ethylderivatives in acetonitrile. In these cases the solvent was evaporatedand the reduction carried out in methanol). Workup A: The reactionmixture was filtered through celite to remove the Pd/C, the cake washedwith acetonitrile (or methanol), and the filtrate evaporated. Theresidue was dissolved in water (approximately 10-15 ml), transferred toa separatory funnel, rendered basic with 10% aqueous Na₂ CO₃ (20 ml) andextracted with methylene chloride (3×40 ml). The extract was dried overMgSO₄ and evaporated, yielding the crude 7-azanorbornanes. Workup B: Thehydrogenation reaction mixture was treated with 1 ml NH₄ OH, dilutedwith an equal volume of methylene chloride (about 30 ml), then filtereddirectly through 20 cc of silica gel in a 30-ml medium fritted glassfunnel. The flask and silica were washed with an additional 2×30 ml of1:1 methylene chloride/acetonitrile (or methanol) containing ˜3-5% NH₄OH, and the combined eluent evaporated, yielding the crude7-azanorbornanes.

EXAMPLE 15 Preparation of2-Carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptanes

These compounds, obtained as a 1:1 mixture of isomers, were prepared in66% overall yield from N-methyl pyrrole and methyl acrylate using themethod set forth in Examples 13 and 14 (workup B). The isomers wereseparated by preparative thin layer chromatography using 1:1:5HMDS/Methanol/methylene chloride: Exo isomer (1): R_(f) =0.76; ¹ H NMR(CDCl₃) δ 3.66 (s, 3H, CH₃ O), 3.62 (d, J=4.2 Hz, 1H, H4), 3.30 (t,J=4.0 Hz, 1H, H4), 2.40 (dd, J=9.6, 5.4 Hz, 1H, H2), 2.21 (s, 3H, CH₃N), 2.18 (m, 1H), 1.86 (m, 2H), 1.57 (dd, J=12.6, 9.6 Hz, 1H,H3_(endo)), 1.33 (m, 2H); ¹³ C NMR (CDCl₃) δ 174.6 (C, CO), 64.2 (CH, C1or C4), 61.1 (CH, C4 or C1), 51.9 (CH₃, CH₃ O), 47.4 (CH, C2), 34.5(CH₃, CH₃ N), 33.3 (CH₂), 26.7 (CH₂), 26.2 (CH₂); Endo isomer (2): R_(f)=0.62; ¹ H NMR (CDCl₃) δ 3.65 (s, 3H, CH₃ O), 3.44 (t, J=4.5 Hz, 1H, H1or H4), 3.21 (t, J=4.5 Hz, 1H, H4 or H1), 3.08 (m, 1H, H2), 2.26 (s, 3H,CH₃ N), 1.95 (m, 1H), 1.75 (m, overlap, 3H), 1.36 (m, 2H); ¹³ C NMR(CDCl₃, 50° C.) δ 174.3 (C, CO), 64.1 (CH, C1 or C4), 62.1 (CH, C4 orC1), 51.4 (CH₃, CH₃ O), 45.2 (CH, C2), 34.4 (CH₃, CH₃ N), 30.6 (CH₂),28.0 (CH₂), 24.2 (CH₂). The picrate salt (both isomers combined) wascrystallized from wet ethanol (m.p. 102-108° C.); Anal. Calcd. for C₁₅H₁₈ N₄ O₉ ; C, 45.23; H, 4.55; N, 14.07. Found: C, 45.42; H, 4.59; N,14.10.

EXAMPLE 16 Preparation of 2-Cyano-7-methyl-7-azabicyclo[2.2.1]heptanes

These compounds, obtained as a 1:1 mixture of isomers, were prepared in57% overall yield from N-methyl pyrrole and acrylonitrile using themethod set forth in Examples 13 and 14 (workup B). The isomers wereseparated by preparative thin layer chromatography, using 1:1:8HMDS/methanol/methylene chloride. Exo isomer (3): R_(f) =0.71; ¹ H NMR(CDCl₃) δ 3.53 (d, J=3.3 Hz, 1H, H1), 3.37 (t, J=3.8 Hz, 1H, H4), 2.44(dd, J=9.3, 5.1 Hz, 1H, H2), 2.36 (s, 3H, CH₃ N), 2.1 (m, 1H), 1.83 (m,2H), 1.75 (dd, J=12.6, 9.3 Hz, 1H, H3_(endo)), 1.3 (m, 2H); ¹³ C NMR(CDCl₃) δ 122.7 (C, CN), 65.5 (CH, C1 or C4), 60.8 (CH, C4 or C1), 35.7(CH₂), 35.3 (CH₃), 31.9 (CH), 27.5 (CH₂), 26.9 (CH₂); Endo isomer (4):R_(f) =0.55; ¹ H NMR (CDCl₃) δ 3.44 (t, J=4.5 Hz, 1H, H1 or H4), 3.29(t, J=4.5 Hz, 1H, H4 or H1), 2.92 (dtd [11 line pattern], J=12, ˜4.8,1.8 Hz, 1H, H2), 2.26 (s, m overlap, 4H, CH₃ N and H3_(exo)), 2.0-1.8(m, 3H), 1.57 (dd, J=12.3, 5.1 Hz, 1H, H3_(endo)), 1.45 (m, 1H); ¹³ CNMR (CDCl₃, 50° C.) δ 121.7 (C, CN), 63.8 (CH, C1 or C4), 61.6 (CH, C4or C1), 34.6 (CH₂), 34.4 (CH₃, CH₃ N), 29.2 (CH, C2), 27.9 (CH₂), 24.1(CH₂). The picrate salt (both isomers combined) was crystallized fromethanol (mp 218-224° C.): Anal. Calcd. for C₁₄ H₁₅ N₅ O₇ : C, 46.03; H,4.14; N, 19.17. Found: C, 45.85; H, 4.08; N, 18.88.

EXAMPLE 17 Preparation oftrans-2,3-Bis-carbomethoxy-7-azabicyclo[2.2.1]heptane

This compound was prepared in 42% overall yield from pyrrole anddimethyl fumarate using the procedures set forth in Examples 11, 12(using acetonitrile as a solvent), and 14 (hydrogenationsolvent--methanol; reaction time--2 h; workup A). ¹ H NMR (CDCl₃) δ 3.95(t, J=4.5 Hz, 1H, H4), 3.84 (d, J=4.8 Hz, 1H, H1), 3.70 (s, 3H, CH₃ O),3.695 (s, 3H, CH₃ O), 3.22 (td, J=4.8, 1.8 Hz, 1H, H3), 3.03 (d, J=4.8Hz, 1H, H2), 2.55 (br s, 1H, NH), 1.8-1.3 (overlapping m, 4H); ¹³ C NMR(CDCl₃) δ 174.8 (C, CO), 172.1 (C, CO), 61.8 (CH, C1 or C4), 59.1 (CH,C4 or C1), 52.3 (CH), 52.1 (CH₃, CH₃ O), 52.0 (CH₃, CH₃ O), 50.1 (CH),28.7 (CH₂), 24.9 (CH₂).

EXAMPLE 18 Preparation ofHexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3(2H)-dione

This compound was obtained as a 4:1 mixture of exo and endo isomers,respectively, in 39% overall yield from pyrrole and N-phenylmaleimideusing the procedures set forth in Examples 11, 12 (using acetonitrile asa solvent), and 14 (hydrogenation solvent--methanol; reaction time--2hours; workup A). The crude material was chromatographed on apreparative thin layer chromatography plate (20×20 cm, 2 mm) using agradient elution of ether containing ˜4% conc. NH₄ OH and 5, 10, and 20%methanol. Two bands were extracted with ether-methanol: F1 (R_(f) =0.75,ether containing 3% NH₄ OH and 10% methanol). This material wasrecrystallized from ethyl acetate-petroleum ether, yielding colorlesscrystals (mp 206-209° C.); exo isomer. ¹ H NMR (CDCl₃) δ 7.5-7.3 (m, 5H,Ph), 4.15 (t, J=2 Hz, 2H, H1, H4), 2.86 (s, 2H, H2, H3), 1.7 (m, 4H,2×CH₂), 1.54 (br s, 1H, NH); ¹³ C NMR (CDCl₃) δ 177.3 (CO), 132.1 (C),129.0 (CH), 128.5 (CH), 126.5 (CH), 59.9 (CH, C1, C4), 49.0 (CH, C2,C3), 29.5 (CH₂). The second fraction (R_(f) =0.21) yielded the endoisomer: ¹ H NMR δ 7.6-7.2 (m, 5H, Ph), 4.18 (br s, 2H, H1 and H4), 3.64(br s, 1H, NH), 3.41 (br s, 2H, H2 and H3), 1.8-1.6 (m, 4H); ¹³ C NMR δ175.9 (C), 132.0 (C), 129.7 (CH), 129.3 (CH), 126.9 (CH), 59.6 (CH),51.5 (CH), 26.5 (CH₂).

EXAMPLE 19 Preparation of8-Ethylhexahydro-2-phenyl-exo-4,7-imino-1H-isoindole-1,3 (2H)-dione

This compound was formed when the synthesis ofhexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3(2H-dione was carried outusing acetonitrile in the hydrogenation step of the method set forth inExample 14 (reaction time--18 h, workup A). The crude material waschromatographed on silica gel (3.5×13 cm column). Elution with etheryielded 56 mg (21%) of the title product (R_(f) =0.8; ether containingNH₄ OH). Further elution with ether containing 10% methanol and 3% conc.NH₄ OH yielded a second fraction containing 69 mg of crudehexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3(2H)-dione (R_(f) =0.2;ether containing NH₄ OH). The first fraction was treated withdecolorizing charcoal, filtered, evaporated, and the residuerecrystallized from ethyl acetate/petroleum ether. Yield=21 mg oflustrous colorless crystals mp 126-128° C. ¹ H NMR (CDCl₃) δ 7.5-7.25(m, 5H, Ph), 3.82 (t, J=2.2 Hz, 2H, H1, H4), 2.80 (s, 2H, H2, H3), 2.37(q, J=7.2 Hz, 2H, NCH₂), 1.93 (m, 2H, H5_(exo), H6_(exo)), 1.51 (m, 2H,H5_(endo), H6_(endo)), 1.04 (t, J=7.2 Hz, 3H, CH₃); ¹³ C NMR (CDCl₃) δ177.8 (CO), 132.4 (C, C1'), 129.1 (CH), 128.5 (CH), 126.7 (CH), 62.6(CH, C1, C4), 49.5 (CH, C2, C3), 40.4 (CH₂ N), 25.0 (CH₂), 14.5 (CH₃).

EXAMPLE 20 Preparation ofHexahydro-1-hydroxy-2-phenyl-4,7-imino-1H-isoindole-3(2H)-one

The exo imide formed in Example 18 (25 mg. ˜0.1 mmol) was treated withexcess sodium borohydride (40 mg, ˜1.0 mmol) in 5 ml ethanol and themixture refluxed for 20 minutes. The ethanol was evaporated, the residueacidified with 1 M HCl, and treated with Na₂ CO₃ and methylene chloride.Evaporation of the extract yielded 20 mg of crude material. Preparativethin layer chromatography (gradient elution; ether containing 5% NH₄ OHand 10-20% methanol) yielded the product (R_(f) =0.25, ether with 3% NH₄OH and 10% methanol), still contaminated with a minor product. ¹ H NMR(CDCl₃) δ 7.55-7.2 (m, 5H, Ph), 5.22 (s, 1H, NCH(OH)), 3.82 (d, J=2 Hz,1H), 2.60 (d, J=2H, 1H), 2.71 (d, J=10 Hz, 1H), 2.08 (d, J=10 Hz, 1H),1.63-1.3 (m, overlap, 6H, 2×CH₂, NH, OH).

EXAMPLE 21 Preparation ofexo-2-aminomethyl-7-methyl-7-azabicyclo[2.2.1]heptane

The nitrile formed in Example 16 (55 mg, 0.4 mmol) was treated withexcess lithium aluminum hydride (30 mg, 0.79 mmol) in 10 ml ether withstirring. After 5 minutes (a white suspension formed), the reaction wasquenched with methanol (0.1 g), then water (0.1 g), acidified with 1 MHCl, then basified with conc., NH₄ OH, and extracted with methylenechloride. Drying and evaporation of the extract yielded thecorresponding primary amine as an oil (17 mg, 30%). ¹ H NMR (CDCl₃) δ3.18 (t, J=3.9 Hz, 1H, H4), 3.03 (d, J=3.9 Hz, 1H, H1), 2.70 (dd, J=12,7.8 Hz, 1H, 1/2 CH₂ N), 2.51 (dd, J=12, 6 Hz, 1H, 1/2 CH₂ N), 2.22 (s,3H, CH₃ N), 1.86 (m, 2H), 1.6-1.2 (m, 7H, CH₂ +NH₂ overlap).

EXAMPLE 22 Preparation ofexo-2-(1-Pyrrolylmethyl)-7-methyl-7-azabicyclo[2.2.1]heptane

The primary amine formed in Example 21 (17 mg, 0.121 mmol) was treatedwith 2,5-dimethoxytetrahydrofuran (25 mg, 0.189 mmol) in acetic acid(0.1 g) at 150° C. for 5 minutes in an oil bath. Extraction of thebasified (10% aqueous Na₂ CO₃) reaction mixture with methylene chlorideyielded a mixture of products from which was obtained 8 mg (˜30%) ofcrude exo-2-(1-pyrrolylmethyl) product by preparative thin layerchromatography using 1:1:8 hexamethyldisilazane/methanol/methylenechloride. ¹ H NMR (CDCl₃) δ 6.68 (s, 2H), 6.18 (s, 2H), 3.92 (dd, J=15,12 Hz, ¹ H, 1/2CH₂ N), 3.72 (dd, J=15, 7 Hz, 1H, 1/2CH₂ N), 3.22 (m,1H), 2.96 (m, 1H), 2.26 (s, 3H, CH₃ N), 1.98 (m, 1H), 1.83 (m, 2H),1.5-1.22 (m, 4H).

EXAMPLE 23 Preparation ofexo-2-Hydroxymethyl-7-methyl-7-azabicyclo[2.2.1]heptane

The aminoester formed in Example 15 (41 mg, 0.243 mmol) was treated withlithium aluminum hydride (10 mg, 0.264 mmol) in 5 ml ether. After 5minutes, the reaction mixture was quenched with methanol, acidified with1 M HCl, basified with conc. NH₄ OH, and extracted with methylenechloride. Evaporation of the extract yielded the desired product (11 mg,32%). ¹ H NMR (CDCl₃) δ 3.80 (dd, J=9, 1 Hz, 1H, 1/2 CH₂ O), 3.39 (dd,J=9, 2 Hz, 1H, 1/2 CH₂ O), 3.21 (t, J=5 Hz, 1H, H4), 3.19 (d, J=4 Hz,1H, H1), 2.18 (s, 3H, CH₃ N), 1.82 (m, 3H), 1.7 (m, 1H), 1.5-1.2 (m,4H).

EXAMPLE 24 Preparation ofexo-2-benzoyloxymethyl-7-methyl-7-azabicyclo[2.2.1]heptane

The alcohol formed in Example 23 (11 mg, 0.078 mmol) was treated withbenzoic anhydride (34 mg, 0.15 mmol) and DMAP (10 mg) in methylenechloride. The product was purified by preparative thin layerchromatography (20×20 cm×0.25 mm) using 1:3:80 NH₄ OH/methanol/ether(R_(f) =0.6). Yield: 10 mg (52%). ¹ H NMR (CDCl₃) δ 8.05 (d, J=7.2 Hz,2H, ortho-H), 7.55 (t, J=7.2 Hz, 1H, para-H), 7.44 (t, J=7.2 Hz, 2H,meta-H), 4.18 (m, 2H, CH2O), 3.22 (t, J=3.9 Hz, 1H, H4), 3.18 (d, J=3.6Hz, 1H, H1), 2.25 (s, 3H, CH₃ N), 2.05-1.85 (m, overlap, 3H), 1.48 (dd,J=12, 9 Hz, 1H, H3_(endo)), 1.34 (m, 3H).

EXAMPLE 25 Preparation of Norbornane Analog of Epibatidine usingReductive Heck Methodology: exo-2-(3-pyridyl) bicyclo[2.2.1]heptane

This procedure is based on that described by R. Larock et al. (J. Chem.Soc. Chem. Comm. 1989, 1368). A mixture of norbornene (101 mg, 1.07mmol), 3-iodopyridine (205 mg, 1.0 mmol), tetra-n-butylammonium chloride(287 mg. 1.03 mmol), potassium formate (255 mg, 3.03 mmol), andpalladium acetate (28 mg, 0.125 mmol) was stirred in DMF (1.2 g) at roomtemperature for 72 hours. The mixture was diluted with 10 ml of 10% Na₂CO₃ (aq) and 10 ml of ether and the aqueous phase extracted again withether. The combined extracts were dried over MgSO₄, filtered andevaporated, and the residue purified by preparative thin layerchromatography (20×20 cm, 2.0 mm, 1:1 petroleum ether/ethyl acetate,Rf=0.5), yielding the title product as an oil (73 mg, 42%). ¹ H NMR(CDCl₃) δ 8.42 (s, 1H, H2'), 8.33 (d, J=4.5 Hz, 1H, H6'), 7.43 (d, J=7.8Hz, 1H, H4'), 7.11 (dd, J=7.8, 4.5 Hz, 1H, H5'), 2.67 (dd, J=8.7, 5.7Hz, 1H, H2), 2.30 (m, 2H, 1H, H1 and H4), 1.8-1.2 (m, overlap, 8H,4×CH₂, ¹³ C NMR (CDCl₃) δ 149.1 (CH), 146.3 (CH), 142.3 (C), 134.0 (CH),122.9 (CH), 44.7 (CH), 42.5 (CH), 38.7 (CH₂), 36.7 (CH), 35.9 (CH₂),30.3 (CH₂), 28.6 (CH₂).

B. SYNTHESIS OF THE 7-AZABICYCLO[2.2.1]-HEPTANE OR -HEPTENE RING SYSTEMUSING DIELS-ALDER APPROACH

In an alternative embodiment, as illustrated in FIGS. 2a and 2b, activecompounds, or their precursors, are prepared through the Diels-Alderreaction of an N-(electron withdrawing-substituted)pyrrole with anarylsulfonyl(optionally substituted aryl or heterocyclic)acetylene. Theelectron withdrawing group at the N⁷ -position decreases the aromaticityof the pyrrole ring and activates the ring in favor of the cycloadditionreaction.

The product of the reaction between the N-(electronwithdrawing-substituted)pyrrole with the arylsulfonyl(optionallysubstituted aryl or heterocyclic)acetylene is a 7-(electron withdrawingsubstituted)-2-(optionally substituted aryl orheteroaromatic)-3-arylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene(compounds 23 and 32, FIG. 2). This diene can be derivatized usingconventional methods to a wide variety of 7-azabicyclo[2.2.1]-heptanesand -heptenes. For example, an R³ alkyl or aralkyl group can be added byreacting the saturated bicycloheptane derivative of compound 23 or 32with n-butyl lithium and R³ I, followed by treatment with a reducingagent to remove the 3-arylsulfonyl moiety. (Julia, M. and Paris, J-M.,Tetrahedron Letters, 49, 4833 (1973).) R⁵ and R⁶ groups can be added tocompound 24 (FIG. 2) by appropriate and conventional reactions of thedouble bond. (See Advanced Organic Chemistry F. A. Carey and R. J.Sundberg (1990) pp. 167-218 Plenum Publishing Co.) Nonlimiting examplesof addition reactions include hydrogenation, hydroboration,hydrohalogenation, hydroxylation, halohydrination, alkylation, carbeneand dihalo carbene addition and epoxidation followed by ring openingreactions with nucleophiles such as alkoxide, amines, alkylsulfide,halide, and hydroxide.

The reactive chloro in compounds 24 and 25 (FIG. 2) is easily displacedby nucleophiles such as alkoxy, including methoxy, alkylthio, hydroxy,amino, cyano, azide, bromide, iodide, and dimethylamino.

The reaction between the N-(electron withdrawing-substituted)pyrrolewith the arylsulfonyl(optionally substituted aryl orheterocyclic)acetylene is carried out in excess N-(electron withdrawingsubstituted)-pyrrole or in a solvent, for example, toluene,tetrahydrofuran, dimethylformamide, diethoxyethane or other inertsolvents. Any molar ratio of pyrrole to dienophile can be used thatprovides an acceptable yield of product, and typically ranges between0.5:1 to 50:1, preferable (1-5):1.

The reaction is conducted at any temperature that produces the desiredproduct, and typically, between room temperature and 150° C., until thereaction is completed, for typically between 1 hour and 72 hours at 1atm. or elevated pressure in a sealed reactor.

Several methods have been investigated for the removal of the N-electronwithdrawing group, and specifically, the N-carbomethoxy protectinggroup, after synthesis of the desired 7-azabicyclo[2.2.1]-heptane or-heptene framework. Hydrolysis of compound 25 (FIG. 2) with potassiumhydroxide in methanol results in substitution of the moderately reactivechlorine in the pyridine ring by a methoxy group. Treatment of 25 withmethyllithium stopped at the formation of N-acetyl epibatidine(identical with an authentic sample from acetylation of rac-epibatidineas described below), which resisted further cleavage by methyllithiumeven after a prolonged treatment. This is in accordance with the knownstability of N-acetyl epibatidine. Compound 25 is successfully deblockedby treatment with hydrobromic acid in acetic acid for 24 hours at roomtemperature. The products isolated from silica gel chromatography, witha mixed solvent system of ethyl acetate, methylene chloride and ammoniain methanol as the eluent, were rac-epibatidine (19, 25%),rac-endo-epibatidine (19', 28.4%) and unchanged carbamate (25, 20%).Notably, the recovered starting material is essentially the pure endoisomer of 25, indicating some stereoselectivity in the cleavage of theN-carbomethoxy group with hydrobromic acid. The exo-isomer wasapparently cleaved at a higher rate than the endo-isomer, presumablyinfluenced by the proximity of the pyridyl group and the carbamategroup. The rac-epibatidine thus obtained, m.p. 50-51°, is very pure, asevidenced by its spectral data.

i). N-(electron withdrawing-substituted)pyrrole

Many substituted pyrroles are known and are easily converted toN-(electron withdrawing-substituted)-pyrroles for use in the Diels-Alderprocess to prepare 7-azabicyclo[2.2.1]heptanes and -heptenes. Forexample, 3-(thioalkyl)pyrrole, including 3-(SCH₃)pyrrole;2,5-dialkylpyrrole, including 2,5-dimethylpyrrole;3,4-dihaloalkylpyrrole, including 3,4-bis(trifluoromethyl)pyrrole,2-alkylpyrrole, including 2-methylpyrrole; 2-alkoxyalkylpyrrole,including 2-methoxymethylpyrrole; 2-alkylthioalkylpyrrole, including2-methylthiomethylpyrrole; 2-dialkylaminoalkylpyrrole, including2-dimethylaminomethylpyrrole; alkyl pyrrole 2-acetate, includingdimethylaminomethylpyrrole; alkyl pyrrole 2-acetate, including methylpyrrole 2-acetate; 2-alkoxyalkoxyalkylpyrrole, including2-methoxymethoxyethylpyrrole; 3-aryloxyalkylpyrrole, including3-benzyloxymethylpyrrole; 2-alkoxypyrrole, including 2-methoxypyrrole;3-alkoxypyrrole, including 3-methoxypyrrole; 3-aryloxypyrrole, including3-benzyloxypyrrole; 3,4-dialkylpyrrole, and 3-alkylpyrrole, including3-methylpyrrole and 3,4-dimethylpyrrole; 1,6 and 4,5-alkylidene pyrrole,including 4,5,6,7-tetrahydroindole and2-methyl-4,5,6,7-tetrahydroindole.

The N-substituent on the pyrrole ring is any moiety that is electronwithdrawing and that activates the ring toward cycloaddition with adienophile. The N-substituent is preferably carbomethoxy, however, otherelectron withdrawing moieties, including carbobenzyloxy,tert-butoxycarbonyl and optically active alkoxycarbonyl, including (+)and (-)-menthyloxycarbonyl can also be used.

ii). Arylsulfonyl(optionally substituted aryl orheteroaromatic)acetylene

In this process, a compound of the formula aryl--SO₂ C.tbd.C--(optionally substituted aryl or heteroaromatic) is reacted with theN-(electron withdrawing-substituted)pyrrole or its derivative.

The arylsulfonyl-(optionally substituted aryl orheteroaromatic)-acetylene can be prepared by methods known to those ofskill in the art. In one embodiment, described in detail in the Example26 below, the compound is prepared by reacting the lithium salt ofmethyl(aryl)sulfone with the desired optionally substituted aryl orheteroaromatic acid chloride to produce a 1-(aryl orheteroaromatic)-2-arylsulfonylethanone, that is converted to thecorresponding acetylene via an enolphosphate intermediate as describedin Example 27 below. Any optionally substituted aryl or heteroaromaticacid chloride can be used, including without limitation, the acidchloride of nicotinic acid, isonicotinic acid, 5-chloronicotinic acid,6-methylnicotinic acid, 6-methoxynicotinic acid, 6-phenylnicotinic acid,6-methylthionicotinic acid, 2-chloropyridine-4-carboxylic acid,2,6-dimethylpyridine-4-carboxylic acid,1-methyl-2(1H)-pyridone-3-carboxylic acid, 6-methylthionicotinic acid,3-quinolinic acid, 4-quinolinic acid, 7-chloro-3-quinolinic acid,6-methoxy-3-quinolinic acid, isoquinoline-4-carboxylic acid,5-chlorothiophene-2-carboxylic acid, pyrimidine-5-carboxylic acid,5-methoxyindole-3-carboxylic acid, 1,2,5-thiadiazole-2-carboxylic acid,thiazole-5-carboxylic acid, 2-chloro-thiazole-5-carboxylic acid, and5-chloropyridazine-2-carboxylic acid. Substituents that can bepositioned on the aromatic or heteroaromatic group include, but are notlimited to, alkyl, halo, aryl, alkoxy, dialkylamino, alkylthio, hydroxy,hydroxyalkyl, and C(O) (alkyl or aryl).

The aryl group attached to the sulfone can be any group thatsufficiently activates the acetylenic group to act as a dienophiletoward the activated pyrrole and which does not interfere with thecycloaddition reaction. Nonlimiting examples are phenyl, p-alkylphenyl,including p-methylphenyl; halophenyl, and including p-chlorophenyl,p-fluorophenyl, and p-nitrophenyl. Fluoroalkanesulfonyl, including CF₃SO₂ and C₄ F₉ SO₂, can also be used to activate an aryl- orheteroarylacetylene.

Methods to prepare a wide variety of arylsulfonyl-(aryl orheteroaromatic)-acetylenes are described in Bhattacharya, S. N., et al,Organomet. Chem. Synth. 1, 145 (1970), and the reaction of an aryl orheteroaromatic trimethylsilyl acetylene (Sakamoto, T., et al.,Synthesis, 312 (1983)) with tosyl chloride in the presence of a Lewisacid catalyst such as aluminum trichloride.

The process for preparing active compounds through the Diels-Alderreaction of an N-(electron withdrawing-substituted)pyrrole with anarylsulfonyl(optionally substituted aryl or heterocyclic)acetylene isset out in detail in the working examples below. These examples aremerely illustrative, and not intended to limit the scope of the processor the compounds that can be made according to the process. As discussedabove, this is a general method that can be combined with conventionalsynthetic techniques to provide a wide variety of products, all of whichare considered to fall within the scope of the invention. The compoundsare numbered as illustrated in FIG. 2.

EXAMPLE 26 Preparation of1-(2-chloro-5-pyridyl)-2-phenylaulfonylethanone (9)

To a cold solution (-30° C.) of 20 g methyl phenyl sulfone in 400 mldried tetrahydrofuran was added 128 ml 2.5M n-butyllithium (2.4 eq)slowly. The resulting solution was stirred at -30° C. for 30 minutes. Asolution of 26 g 6-chloronicotinyl chloride in 100 ml tetrahydrofuranwas then added during a 20 minute period. After stirring at the sametemperature for 30 minutes, the mixture was quenched by addition of sat.ammonium chloride (ca. 100 ml). The organic layer was separated and theaqueous layer extracted with chloroform three times. The combinedorganic layer was washed with sat. brine and dried over magnesiumsulfate. After removal of solvent, the brown solid was triturated withmethanol (150 ml) to give 7.06 g of a slightly yellow solid. Anothercrop of the product (11.75 g) was obtained from the mother liqueur bychromatography on a short silica gel column using 50% ethyl acetate inpetroleum ether as the eluent. The total yield is 18.81 g (49.7%). m.p.152-3° C. MS(CI) m/z 296, 298(M+1).

In a similar manner, when the acid chlorides of nicotinic acid,isonicotinic acid, 5-chloronicotinic acid, 6-methylnicotinic acid,6-methoxynicotinic acid, 6-phenylnicotinic acid, 6-methylthionicotinicacid, 2-chloropyridine-4-carboxylic acid,2,6-dimethylpyridine-4-carboxylic acid,1-methyl-2(1H)pyridone-3-carboxylic acid, 6-methylthionicotinic acid,3-quinolinic acid, 4-quinolinic acid, 7-chloro-3-quinolinic acid,6-methoxy-3-quinolinic acid, isoquinoline-4-carboxylic acid,5-chloro-thiophene-2-carboxylic acid, pyrimidine-5-carboxylic acid,5-methoxyindole-3-carboxylic acid, 1,2,4-thiadiazole-2-carboxylic acid,thiazole-5-carboxylic acid, 2-chloro-thiazole-5-carboxylic acid,5-chloropyridazine-2-carboxylic acid are used in place of6-chloronicotinyl chloride in the condensation reaction, thecorresponding ketosulfones are obtained.

EXAMPLE 27 Preparation of 2-chloro-5-pyridyl phenylsulfonyl acetylene(22)

A solution of 3.34 g (11.3 mmol) of 20 in 100 ml dried tetrahydrofuranwas added to a suspension of 840 mg 60% sodium hydride (washed withethyl ether) in 100 ml tetrahydrofuran. After stirring 10 minutes, 1.88ml (11.3 mmol) diethyl chlorophosphate was added in one portion. Themixture was stirred at room temperature overnight, then cooled to -78°C., and 1.35 g potassium t-butoxide is added in portions. The brownsolution was stirred at -78° C. for another 10 minutes and allowed towarm to ca. -30° C. Water was added and the aqueous layer extracted withmethylene chloride. After drying and evaporation in vacuo, the residuewas purified on a silica gel column, and eluted with 25% ethyl acetatein petroleum ether. The white solid (1.2 g) obtained after evaporationof solvent has a m.p. 140-141° C. MS(CI) m/z 278, 280(M+1), yield 38%.

In a similar manner, when other heterocyclic ketosulfones described inExample 26 are used in place of compound 20, the correspondingacetylenes are obtained.

EXAMPLE 28 Preparation of N-carbomethoxy pyrrole (21)

Potassium (5.85 g, 0.15 mol) was added to a solution of 10 ml pyrrole(0.145 mol) in 80 ml hot cyclohexane in several portions. The mixturewas refluxed for 1 hour. To this cold solution was added 15 g (0.16 mol)methyl chloroformate slowly. After addition, the mixture was stirred atroom temperature for 30 minutes. During this period, 2.5 ml dimethylsulfoxide was added for catalysis. After quenching with ice-water, theorganic layer was separated and the aqueous layer extracted with ether.The combined organic layer was washed with 10% sodium bicarbonate, sat.sodium chloride and dried over magnesium sulfate. Removal of solventyielded 17.4 g of a liquid. Bulb to bulb distillation gives 16.5 gN-carbomethoxy pyrrole 21 as a colorless liquid, yield 91%. The productrequires storage at -20° C.

In a similar manner, the N-carbomethoxy, N-carbobenzyloxy andN-tert-butoxycarbonyl derivatives of 2,5-dimethylpyrrole,3,4-bis(trifluoromethyl)pyrrole, 2-methylpyrrole,2-methoxymethylpyrrole, 2-methylthiomethylpyrrole,2-dimethylaminomethylpyrrole, methyl pyrrole-2-acetate,2-methoxymethoxyethylpyrrole, 3-benzyloxymethylpyrrole,2-methoxypyrrole, 3-methoxypyrrole and 3-benzyloxypyrrole are prepared.

EXAMPLE 29 Preparation of7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]-2,5-diene(23)

2-Chloro-5-pyridyl phenylsulfonyl acetylene 22 (1.12 g, 40.3 mmol) wasdissolved in 8.0 g N-carbomethoxy pyrrole 21. The mixture was stirred ina covered flask at 80-85° C. for 24 hours. After evaporation in vacuo torecover N-carbomethoxy pyrrole, the residue was chromatographed on asilica gel column using 25% to 50% ethyl acetate in petroleum ether aseluent to recover 0.2 g of the acetylene 22 and obtain 1.21 g of aslightly dark product. The crude product was triturated with methanol toyield 0.94 g (58% or 70% according to recovered starting material) of awhite solid. m.p. 101° C. MS(CI) m/z 403, 405 (M+1). When thearylsulfonyl acetylene derivatives described in Example 27 are used inplace of compound 22 in this experiment, the corresponding Diels-Alderadducts are obtained.

EXAMPLE 30 Preparation of7-carbomethoxy-5-(2-chloro-5-aza-bicyclo[2.2.1]hept-2-ene (24)

Compound 23 (0.726 g, 1.9 mmol) was dissolved in 50 ml anhydrousmethanol and 7 ml dried tetrahydrofuran containing 1.0 g (8.0 mmol) ofsodium dihydrophosphate. To this mixture was added 3.0 g 6% sodiumamalgam in two portions at -20° C. under nitrogen. The stirred mixturewas allowed to warm spontaneously to room temperature during a 2 hourperiod and stirred at room temperature for another hour. The upper layerwas decanted and the residue washed with methanol. Water and 10% HClwere added to the combined methanolic extracts to bring the pH to 6 andmost of the methanol removed in vacuo. The mixture was then extractedwith methylene chloride. The combined organic layer was washed with sat.brine and dried over magnesium sulfate. After removal of solvent, theresidue was purified on a silica gel column using 33% ethyl acetate inpetroleum ether as the eluent to yield 215.3 mg (42.9%) of a colorlessoil. ¹ H-NMR shows that it is a (1:2) mixture of exo and endo isomers.MS (CI) m/z 265, 267 (M+1). ¹ HNMR 6.01-6.53(2H, H₅,6), 4.61-4.91(2H,H₁,4). When other Diels-Alder adducts described in Example 29 aretreated with sodium amalgam in a similar manner, the correspondingsubstituted 7-aza-bicyclo[2.2.1]hept-2-enes are obtained.

EXAMPLE 31 Preparation of7-carbomethoxy-2-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]heptane (25)

Compound 24 (178.4 mg, 0.674 mmol) (mixture of isomers) was dissolved in10 ml methanol containing 5 mg 10% Pd-C. The mixture was hydrogenatedunder 1 atm. of hydrogen. After 18 ml of hydrogen was absorbed (5minutes), the catalyst was removed by filtration and methanol removed invacuo to give 165 mg (92%) of colorless oil. ¹ H-NMR indicates that itis a (1:2) mixture of exo and endo isomers. MS(CI) m/z 267, 269 (M+1). ¹H-NMR 4.21-4.44(2H, H₁,4). In a similar manner, other substituted7-aza-bicyclo[2.2.1]hept-2-enes described in Example 30 are hydrogenatedto the corresponding substituted 7-aza-bicyclo[2.2.1]heptane analogs.

EXAMPLE 32 Preparation of racemic epibatidine (19) and endo-epibatidine(19')

Compound 25 (90 mg, 0.338 mmol) was dissolved in 2.5 ml hydrobromic acid(33% in acetic acid). The mixture was stirred at room temperature for 20hours. After evaporation of the mixture in vacuo the residue wasdissolved in water and extracted with ethyl ether to recover thestarting material (26 mg). The aqueous layer was neutralized withpotassium hydroxide to pH 11 and extracted with methylene chloride. Thecombined organic layer was washed with saturated brine and dried overmagnesium sulfate. After removal of the solvent, the 56 mg residue waschromatographed on silica gel column using ethyl acetate, methylenechloride and sat. ammonia methanol (2:1:0.03) to give 18 mg (25%) ofepibatidine (19) m.p. 50-51° and 20 mg (28.4%) of endo-epibatidine(19'). The spectral data for these compounds is provided in Table 3.

                  TABLE 3                                                         ______________________________________                                        Spectra data for epibatidine (19) and endo-epibatidine (19')                              epibatidine (19)                                                                           endo-epibatidine (19')                               ______________________________________                                        MS(CI)m/z   209,211(M + 1)                                                                             209,211(M + 1)                                         H.sup.1 -NMR                                                                  H.sub.1.4,       3.80(t, 3.9Hz),     3.76(q, 4.8Hz)                                         3.56(br.s)                                                      H.sub.3e        1.90(dd, 12.0,    2.12(tdd, 12.3, 4.8,                                       9.0Hz)             3.3Hz)                                    ______________________________________                                    

The N-acetyl derivatives of epibatidine can be prepared from epibatidineand acetic anhydride in the presence of triethylamine. Likewise, otherN-substituted 7-azabicyclo[2.2.1]heptanes described in Example 31 aredeprotected to the corresponding free amine. The amines are readilyacylated to the amide, alkylated to the tertiary amine and quaternaryammonium derivatives by using conventional methods. The amines also formstable and water-soluble salts with organic and inorganic acids aspreferred in the pharmaceutical formulation.

EXAMPLE 33 Preparation of7-carbomethoxy-2-(2-methoxypyridyl)-7-aza-bicyclo[2.2.1]heptane (29)

7-Carbomethoxy-2-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]heptane 25 (20mg, 0.076 mmol) was dissolved in 1.0 ml methanol containing 12.8 mg (0.2mmol) potassium hydroxide. The mixture was refluxed for one hour, thenconcentrated and partitioned between ethyl ether and water. The aqueouslayer was extracted with ether again and the combined organic layer waswashed with sat. sodium bicarbonate, and dried over magnesium sulfate.Removal of solvent yielded a 10 mg residue. H¹ -NMR shows it is a 1:2mixture of exo and endo isomers of the title compound. H¹ -NMR 3.92,3.90(2s, Py-OCH₃), 3.71, 3.66(2s, NCOOCH₃).

EXAMPLE 34 Preparation of deschloro analogues of epibatidine (30)

N-carbomethoxy-5-(2-chloro-5-pyridyl)-7-aza-bicyclo[2.2.1]hept-2-ene 25(16 mg) was dissolved in 3 ml methanol containing 7 mg 10% palladium oncarbon. The mixture was hydrogenated under a slightly elevated pressureof hydrogen for one hour. After removal of catalyst and solvent, theresidue was partitioned between ether and aqueous sodium bicarbonate.The aqueous layer was extracted with ether and the combined organiclayer was dried over magnesium sulfate. Removal of solvent gave 10 mg of7-carbomethoxy-2-(3-pyridyl)-7-azanorbornane (12). MS (CI) m/z 233(M+1), H¹ -NMR 3.72, 3.66 (2s, N-COOCH₃).

EXAMPLE 35 Preparation of 5,6-dehydro analogs of epibatidine

When the N-acylated 7-aza-bicyclo[2.2.1]hept-5-ene derivatives preparedin Example 30 are acid hydrolyzed under conditions similar to thatdescribed in Example 32, the corresponding 5,6-dehydro analogs ofepibatidine (19) and its endo-isomer (19') are obtained.

EXAMPLE 36 Preparation of1,4-dimethyl-2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-7-carbomethoxy-7-aza-bicyclo[2.2.1]hept-2,5-diene

A mixture of 0.14 g (0.5 mmol) 2-chloro-5-pyridyl phenylsulfonylacetylene(22) and 0.7 g 2,5-dimethyl-N-carbomethoxypyrrole (31) washeated and maintained at 85° C. for 48 hour. The excess pyrrole (31) wasremoved in vacuo and the dark residue chromatographed on silica gelusing 25%-33% ethyl acetate in petroleum ether as eluent, yielding 76 mg(35%) of the title compound. MS(CI) m/z 431, 433 (M+1). H¹ -NMR 6.79,6.55 (AB J=5.4Hz, H₅,6), 3.52(s, 3H, N--COOCH₃), 1.96, 1.68(2s, 6H,2CH₃).

EXAMPLE 37 Preparation of benzoyl phenylsulfonyl methane (32)

A procedure similar to the preparation of compound 20 was used. Theproduct was obtained in 60% yield as a white crystal (crystallized fromcarbon tetrachloride). m.p. 91-93° C. (lit, m.p. 93-94° C.).

When the acid chloride of 4-chlorobenzoic acid, 3-methoxybenzoic acid,3,4-methylenedioxybenzoic acid, 3,4,5-trimethoxybenzoic acid,3-trifluoromethylbenzoic acid, 3-dimethylaminobenzoic acid,4-methylthiobenzoic acid, 4-methylsulfinylbenzoic acid,4-methylsulfonylbenzoic acid, 3,5-difluorobenzoic acid, 2-naphthoicacid, 4-dimethylamino-2-naphthoic acid, 6-methoxy-2-naphthoic acid,2-phenylpropionic acid and 2-(3,4-methylenedioxyphenyl) propionic acidare used in place of benzoyl chloride above, the correspondingsubstituted ketosulfones are prepared.

EXAMPLE 38 Preparation of phenyl phenylsulfonyl acetylene (34)

A procedure similar to the preparation of compound 22 was used.Chromatography of the crude product on silica gel using 5% ethyl acetatein petroleum ether as the eluent yielded 20% of the acetylene 34 as asolid.

Using a similar procedure, the other ketosulfones described in Example37 are converted to the corresponding substituted aryl and aralkylacetylenic derivatives.

EXAMPLE 39 Preparation of7-carbomethoxy-2-phenyl-3-phenylsulfonyl-7-azanorborna-2,5-diene (35)

Phenyl phenylsulfonyl acetylene 34 (84.3 mg, 0.35 mmol) was mixed with0.42 g of N-carbomethoxy pyrrole (21). The mixture was heated to andmaintained at 85° C. for 48 hours. After removal of the excess pyrrole,the residue was chromatographed on silica gel column and eluted with25-33% ethyl acetate in petroleum ether to give 30 mg (23%) of theadduct as a colorless oil. MS(CI) m/z 368(M+1). H¹ -NMR 7.05(s, 2H,H₅,6), 5.51, 5.48(2s, 2H, H₁,4), 3.5(br.s. 3H, N--COOCH₃).

Using a similar procedure, cycloadditions of substituted pyrrolesdescribed in Example 28 and substituted acetylenic derivatives preparedin Example 38 give the corresponding 7-aza-bicyclo[2.2.1]hepta-2,5-dieneadducts.

EXAMPLE 40 Preparation of 2-phenyl-7-aza-bicyclo[2.2.1]heptane (36)

The bicyclic adduct 35 was reductively desulfonated, hydrogenated andacid hydrolyzed as described in Examples 30, 31 and 32 to yield 36.similarly, the other bicyclic adducts in Example 39 are converted to thecorresponding 2-substituted aryl-7-aza-bicyclo[2.2.1]heptanes.

EXAMPLE 41 Preparation of 2-phenyl-7-aza-bicyclo[2.2.1]hept-5-ene (37)

The bicyclic adduct 35 is reductively desulfonated and acid hydrolyzedas described in Examples 30 and 32 to yield 37. Similarly, the otherbicyclic adducts in Example 39 are converted to the corresponding2-substituted aryl-7-aza-bicyclo[2.2.1]hept-5-enes.

EXAMPLE 42 Preparation of 5 and/or 6 substituted 2-aryl (orheteroaryl)-7-aza-norbornanes from the corresponding 7-N-acyl or7-aza-2-aryl (or heteroaryl)-norborn-5-enes

The 5 and/or 6-substituents are introduced by functioning the 5,6-doublebond through conventional reactions, e.g., additions, hydroboration,epoxidation followed by ring opening with nucleophiles (alkoxide, amine,azide, alkylsulfide, halide, hydroxide, etc.).

EXAMPLE 43 Preparation of3-methyl-7-aza-2-exo-(2-chloro-5-pyridyl)bicyclo[2.2.1]heptane (38)

7-Carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2,5-diene(23) is hydrogenated in methanol containing 10% Pd-C until both doublebonds are saturated. The product,7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]heptane39, is dissolved in dry tetrahydrofuran and treated with n-butyl lithium(1.1 eq) at -30 to 0° C., followed by methyl iodide (1-1 eq) intetrahydrofuran. The reaction mixture is then stirred at roomtemperature and poured into iced water. The product is extracted withether and washed with water. After drying and evaporation of the ethersolution, the crude product is chromatographed on a silica gel column,using a mixture of petroleum ether and ethyl acetate (3:1 by volume) toyield stereoisomers of7-carbomethoxy-2-(2-chloro-5-pyridyl)-3-methyl-3-phenylsulfonyl-7-aza-bicyclo[2.2.1]heptane(40).The alkylation products are each treated with sodium amalgam as inExample 30 to remove the phenylsulfonyl group, followed by acid cleavageof the 7-carbomethoxy group as in Example 32 to yield isomeric 3-methylanalogs of compound 8 and 8'.

Similarly, when methyl iodide is replaced by ethyl bromide, allylbromide, benzyl chloride, methoxymethyl chloride and methoxyethylmethanesulfonate, and corresponding 3-ethyl, 3-allyl, 3-benzyl,3-methoxymethyl and 3-methoxyethyl derivatives are obtained.

Other 2-aryl or 2-heteroaryl derivatives of7-N-acyl-7-aza-3-phenylsulfonyl-bicyclo[2.2.1]hepta-2,5-diene describedin Example 29 are likewise hydrogenated, converted to the sulfonylcarbanion, alkylated, desulfonated and deacylated to give thecorresponding 3-alkyl or aralkyl analogs.

EXAMPLE 44 Preparation of7-methyl-7-aza-2-exo-(2-chloro-5-pyridyl)bicyclo[2.2.1]heptane (41)

Epibatidine 19 prepared in Example 32 is alkylated with methyl iodide(1.1 eq) in dry tetrahydrofuran at room temperature, followed by theusual isolation procedure, to give the 7-N-methyl derivative.

Similarly, alkylation with ethyl iodide, isopropyl bromide, allylbromide, cyclopropylmethyl bromide, benzyl chloride, 4-methoxybenzylchloride, 3,4-dimethoxybenzyl chloride, phenethyl bromide, propargylbromide, hydroxyethyl chloride and methoxyethyl iodide yield thecorresponding 7-N-alkylated derivatives.

Other substituted 7-aza-bicyclo[2.2.1]heptane analogs described in theexamples above are alkylated to their 7-N-alkyl is derivatives in thesame manner.

The N-acetyl derivative of epibatidine in Example 7 is reduced to theN-ethyl derivative by the treatment of lithium aluminum hydride in drytetrahydrofuran at room temperature. Similarly, the 7-N-propionyl,N-benzoyl, N-phenylacetyl and N-2-furoyl derivative of epibatidine arereduced to the corresponding 7-propyl, 7-benzyl, 7-phenethyl and7-(2-furfuryl) derivatives.

EXAMPLE 45 Resolution of racemic compounds

The substituted 7-aza-bicyclo[2.2.1]heptane derivatives are resolved totheir optical isomers by conventional methods including chromatographyon a chiral column, fractional crystallization of diastereomeric saltsof chiral acids and separation of the chiral ester or amide derivativesfollowed by regeneration of the optically pure enantiomers. (See OpticalResolution Procedures for Chemical Compounds, Vol. 1, Amines. by P.Newman, 1980 Optical Resolution Information Center, N.Y. 10471.)

EXAMPLE 46 Resolution of racemic epibatidine (19)

To a solution of racemic epibatidine 19 and triethylamine (1.1 eq) inmethylene chloride is added (-)-menthyl chloroformate (1.1 eq). Thereaction mixture is stirred at room temperature for 6 hours, washed withiced water and dried over magnesium sulfate. After evaporation ofsolvent, the residue is chromatographed on a silica gel column, using amixture of petroleum ether and ethyl acetate (5:1 by volume) to yield amixture of two diastereoisomers of 7-N-(-)-menthyloxycarbonylderivatives of d- and l-epibatidine. Separation of the diastereoisomersby HPLC on a chiral column and treatment of each isomer with HBr/AcOH asin Example 32 yields the corresponding d and l-epibatidine.

EXAMPLE 47 Preparation of optical isomers of substituted7-aza-bicyclo[2.2.1]heptane derivatives from chiral intermediates

N-carbo-(-)-menthyloxy pyrrole is prepared from pyrrole and (-)-menthylchloroformate by the method described above. The chiral pyrrole istreated with the sulfonyl acetylene 22 or 34 as in Example 29 to give adiastereoisomeric mixture of the chiral cycloadduct7-aza-bicyclo[2.2.1]hepta-2,5-diene derivative. After treatment withsodium amalgam as in Example 30, the diastereoisomeric mixture of2-exo-aryl-7-aza-bicyclo[2.2.1]hepta-5-ene derivatives is obtained.These diastereomers are separated by chromatography to give the d and lenantiomers. The optically active intermediates are each reduced andtreated with HBr/AcOH to yield optically active epibatidine enantiomers.Similarly, other substituted 7-aza-bicyclo[2,2,1]heptane analogs areprepared from the corresponding chiral pyrroles and chiral cycloadducts.

EXAMPLE 48 Preparation of benzo[5a,6a] epibatidine (39)

Scheme 4 illustrates the preparation of compound 39. ##STR18##

a) Preparation of N-methanesulfonyl isoindole (40)

Sodium hydride (0.88 g) was suspended in 3 ml dimethyl formamide. Tothis stirred solution was added methanesulfonamide (0.95 g, 10 mmol) in5 ml dimethyl formamide dropwise under nitrogen. After stirring at 60°C. for 0.5 hours, a solution of 2.64 g (10 mmol) α,α'-dibromo-o-xylenein 7 ml DMF was added at a rate appropriate to maintain the temperatureat 60-70° C. The mixture was stirred at room temperature for anotherhour, then quenched by pouring into water. The resulting precipitate wascollected and washed with water, petroleum ether and ether successively.Weight 1.57 g (80%). ¹ H-NMR 62.37 (s, 3H, --CH₃), 4.709 (s, 4H, 2CH₂).7.25˜7.35 (m. 4H, ArH).

b) Preparation of2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-1,4-dihydronaphthalene-1,4-imine(41)

Potassium t-butoxide (560 mg, 5.0 mmol) was dissolved in 3 ml DMSO undernitrogen. To this stirred solution was added 197 mg (1.0 mmol)N-methanesulfonyl isoindole in portions. After addition, the mixture wasstirred at room temperature for 1.5 hours and quenched by addition of 3ml water. After extraction with 45 ml ether, the combined organic layerwas washed with saturated brine and dried over magnesium sulfate for 10minutes. After filtration, the filtrate was combined with 83 mg (0.3mmol) 1-(6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene 22. The reactionmixture was stirred at room temperature overnight to evaporate in vacuoand chromatographed on silica gel column. Eluting with a mixed solvent(ethyl acetate, methylene chloride and ammonia in methanol) gave 108 mgblue residue. The color material was removed by washing the acidifiedmaterial. After basification and extraction with ether, 62 mg of purecompound 41 was obtained as a foam. Yield 52%. MS(CI), 395, 397(M+1). ¹H-NMR (CDCl₃): δ5.242(d, J=1.5Hz, 1H), 5.362 (d, J=0.9Hz, 1H). (H₁ orH₄).

c) Preparation of exo and endo-benzo [5a,6a]epibatidine (39)

Compound 41 (54 mg, 0.137 mmol) was dissolved in a mixture of 3 mlmethanol and 1 ml tetrahydrofuran. The solution was cooled to -20° C.and 66 mg 6% sodium amalgam was added. The mixture was stirred for 2hours. The excess reagent was decomposed by water and the liquid layerwas decanted out. After concentration of the liquid in vacuo, theresidue was extracted with methylene chloride (3×5 ml). The combinedorganic layer was washed with saturated brine and dried over magnesiumsulfate. After removal of solvent, the residue was separated onpreparative thin layer chromatography with 33% methylene chloride inethyl acetate to give 5.5 mg exo-benzo [5a,6a] epibatidine and 8.5 mgendo-benzo [5a,6a] epibatidine. Both isomers are an oil. Yields are 15%and 25% respectively. MS(CI), 257, 259(M+1). ¹ H-NMR (CDCl₃), (forexoisomer). 2.753 (dd, J=4.8, 8.4 Hz, 1H, H₂), 4.371 (s, 1H, H₁), 4.656(d, J=4 Hz, 1H, H₄).

EXAMPLE 49 Preparation of N-methyl-benzo [5a,6a] epibatidine (42)

Scheme 5 illustrates a method for the production of N-methyl-benzo [5a,6a] epibatidine 42. ##STR19##

a) Preparation of N-methyl isoindole (43)

N-methyl isoindole was prepared according to the method set forth in B.Zeeh and K. H. Konig, Synthesis 1972, 45.

b) Preparation of2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-1,4-dihydronaphthalene-1,4-imine(44)

N-methyl isoindole (91 mg, 0.7 mmol) was mixed with1-(6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene 22 (139 mg, 0.5 mmol)in ethyl ether. After stirring at room temperature for 1 hour, themixture was concentrated and chromatographed on silica gel column,eluting with ethyl acetate. This gave 204 mg of compound 44 as a clearoil. Yield 100%. MS(CI), 409, 411(M+1). H¹ -NMR (CDCl₃). δ 2.36 (br, 3H,NCH₃), 4.805 (s, 1H), 4.93 (br.s., 1H), (H₁, or H₄).

c) Preparation of N-methyl-benzo [5a,6a] epibatidine (42)

Compound 44 (125 mg, 0.306 mmol) was dissolved in 10 ml methanoltogether with 4 ml tetrahydrofuran. The solution was cooled to -20° C.and 216 mg sodium dihydrophosphate was added to the solution followed by1.0 g 6% sodium amalgam. The mixture was then stirred at roomtemperature for 3 hours and quenched with water. The organic layer wasdecanted out and concentrated in vacuo. The residue was extracted withmethylene chloride (2×10 ml). The combined organic layer was washed withsaturated brine and dried over magnesium sulfate. After removal ofsolvent, the residue was chromatographed on silica gel column elutingwith 50% ethyl acetate in petroleum ether. This gave 19 mg (19%)exo-N-methyl-benzo[5a,6a]epibatidine. Further elution with a mixedsolvent (ethyl acetate, methylene chloride and ammonia in methanol)yielded 55 mg (66%) of the endo-isomer. Total yield 85%. MS(CI), 271,273(M+1). H¹ -NMR (CDCl₃), (for exoisomer): 2.679 (dd, J=4.5, 8.7Hz, 1H,H₂), 3.935 (s, 1H, H₁), 4.203 (d, J=4.0Hz, 1H, H₄), 2.072 (s, 3H, NCH₃).

EXAMPLE 50 Preparation of N-formamidinyl epibatidine dihydrochloride(45)

Scheme 6 shows the preparation of compound 45. ##STR20##

Racemic-epibatidine 19 (42 mg, 0.2 mmol) was mixed with 77 mg (0.7 mmol)freshly prepared ethyl formamidinate hydrochloride and 129 mg (1.0 mmol)diisopropyl ethylamine in 1 ml acetonitrile. After stirring at roomtemperature for 48 hours, the mixture was acidified with 1.0 M hydrogenchloride in ether. After evaporation in vacuo, the residue was separatedon silica gel preparative thin layer chromatography, using a solventsystem of 25% methanol in chloroform, to give 25 mg of the compound 45as a hygroscopic solid. Yield 36%. MS(CI), 236, 238 (free base M+1). H¹-NMR (CD₃ OD). δ 3.40 (M, 1H, H₂).

EXAMPLE 51

The process of Example 50 was repeated with the replacement of ethylformamidinate by S-methyl pseudothiourea, S-methyl-N-methylpseudothiourea, S-methyl-N-nitro pseudothiourea, or methyl acetamidinateto form the N-guanidyl, N-methylguanidyl, N-nitroguanidyl andN-acetamidinyl epibatidine.

EXAMPLE 52 Preparation of N-formamidinyl deschloroepibatidinedihydrochloride (46) ##STR21##

N-Formamidinyl epibatidine (12 mg, 0.04 mmol) 45 was dissolved in 2 mlmethanol containing 5 mg 10% palladium on carbon. After hydrogenationunder 1 atm hydrogen for 3 hours, the catalyst was removed byfiltration. The filtrate was concentrated in vacuo to give 10 mgcompound 46 as a hygroscopic solid. Yield 100%. MS(CI), 202(M+1 -2HCl).H¹ -NMR (CD₃ OD), δ 3.5 (M, 1H, H₂).

EXAMPLE 53 Preparation of 1-methyl epibatidine (47), and 4-methylepibatidine (48) ##STR22## a) Preparation of 2-methylpyrrole (49)

2-Methylpyrrole was prepared according to the method set forth in J.Org. Chem. 28, 3052.

b) Preparation of N-t-butoxycarbonyl-2-methylpyrrole (50)

2-Methyl pyrrole (2.5 g) was dissolved in 6 ml tetrahydrofuran, and wasslowly added to a suspension of 2.4 g 60% sodium hydride (washed withether) in 30 ml tetrahydrofuran. A solution of 7.6 gdi-t-butyl-dicarbonate in 20 ml of the same solvent was added to thiscooled mixture. After shaking occasionally for 3 hours, it wasdecomposed carefully with water, and extracted with ether. The combinedorganic layer was washed with saturated brine and dried over magnesiumsulfate. Removal of the solvent gave 6 g residue. Bulb-to-bulbdistillation gave 4.5 g slightly yellow oil (ca. 80° C./5 mmHg). Yield80%. MS(CI), 183(M+2). H¹ -NMR (CDCl₃) δ 1.584 (s, 9H, 3CH₃), 2.421 (s,3H, CH₃).

c) Preparation of 1- (and 4)-methyl-2-(6-chloro-3-pyridyl)-3-phenylsulfonyl-7-t-butoxycarbonyl-7-azanorborna-2,5-diene(51)

Compound 50 (10 mmol, 1.8 g) was mixed with1-(6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene (22) 555 mg (2.0mmol). The mixture was heated at 78° C. in a tightly covered flask undernitrogen for 24 hours. The mixture was separated on silica gel columneluting with 25% of ethyl acetate in petroleum ether. After recovery of1.5 g of compound 50 and 120 mg compound 22, 636 mg of compound 51 wasobtained as a yellow oil. Yield 69.3%. ¹ H-NMR showed that the oil is a2:1 mixture of 1-methyl isomer and 4-methyl isomer. MS(CI), 459, 461.(M+1). H¹ -NMR (CDCl₃), (for major isomer): 1.37 (s, 9H, 3CH₃), 1.748(s, 3H, CH₃), 5.45 (d, J=3Hz, 1H, H₄). (For the minor isomer), 1.346 (s,9H, 3CH₃), 1.958 (s, 3H, CH₃), 5.26 (d, 1H, J=3Hz, H₁).

d) Preparation of N-t-Boc-1 (and 4) -methyl epibatidine (52)

Compound 51 (1.0 mmol, 459 mg) was dissolved in a mixture of 20 mlmethanol and 10 ml tetrahydrofuran. The solution was stirred and cooledto -20° C. To this solution was added 720 mg sodium dihydrophosphatefollowed by 1.5 g (6.0 mmol) 6% sodium amalgam. After stirring at roomtemperature for 2 hours, another 0.8 g of 6% sodium amalgam was addedand stirring was continued for another 2 hours. The excess reagent wasdecomposed by water, and the solution was decanted out. Afterconcentration of the solution at ambient temp in vacuo, the residue wasextracted with methylene chloride (4×15 ml). The combined organic layerwas washed with saturated brine and dried over magnesium sulfate. Afterremoval of solvent, the residue (372 mg) was hydrogenated under 1 atmhydrogen in the presence of 8.4 mg platinum oxide for 2 hours. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo to a residue (360 mg). Separation took place on a silica gelcolumn eluting with 17% ethyl acetate in petroleum ether. 95 mg of theendo-isomers and 65 mg of the exo-isomers were obtained. Total yield50%. MS(CI), 323, 325 (M+1). H¹ -NMR (CDCl₃) (for exo isomer major),2.78 (dd, 1H, J=5.4Hz, 7.8Hz, H₂), 4.45 (t, 1H, J=4.5Hz, H₄).

e) Preparation of 1-methyl epibatidine (47) and 4-methyl epibatidine(48)

The exo-isomer of compound 52 (65 mg) was dissolved in 5 ml methylenechloride. To this--cooled solution (0° C.) was added 2.5 mltrifluoroacetic acid. The resulting pink solution was then stirred atroom temperature for 1.5 hours. After neutralization with 4.5 gpotassium carbonate in 10 ml water, the organic layer was separated andthe aqueous layer was extracted with methylene chloride. The combinedorganic layer was washed with saturated brine and dried over magnesiumsulfate. Removal of solvent and separation on silica gel preparativethin layer chromatography developing with a mixed solvent (ethylacetate, methylene chloride and ammonia in methanol) gave 6 mg of4-methyl epibatidine 48 and 12 mg 1-methyl epibatidine 47. Total yield40.2% MS(CI), 223, 225 (M+1). H¹ -NMR (CDCl₃), (for 1-methylepibatidine, major, exo-isomer). δ 2.657 (dd, J=4.8, 8.7Hz, 1H, H₂),3.694 (t, J=4.7Hz, 1H, H₄). (For 4-methyl epibatidine, minorexo-isomer): 2.887 (dd, J=4.7Hz, 1H, H₂), 3.486 (d, J=4.5Hz, 1H, H₁).

EXAMPLE 54 Preparation of 2-(2-fluoro-5-pyridyl)-7-azanorbornane (53)##STR23## a) Preparation of 1-(2-fluoro-5-pyridyl)-2-phenylsulfonylethanone (54)

The method set forth in Example 26 was used, replacing 6-chloronicotinylchloride with 6-fluoronicotinyl chloride (see Anderson et al; J. Med.Chem, 1990, 33(6) 1667), providing compound 54 as a white crystal, mp.127-128° C. Yield 72%. MS(CI), 280(M+1). H¹ -NMR (CDCl₃). δ 2.70 (s, 2H,CH₂).

b) Preparation of 1-(2-Fluoro-5-pyridyl)-2-phenylsulfonyl acetylene (55)

Use of the method set forth in Example 27 gave compound 55 in 62% yieldfrom compound 54 as a white solid. mp. 97-98.5° C. MS(CI) 262(M+1).

c) Preparation of7-carbomethoxy-2-(2-fluoro-5-pyridyl)-3-Phenylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene(56)

Use of the method set forth in Example 29 gave compound 56 in 66% yieldplus 22% of recovered acetylene 55. Compound 56 is a white cubiccrystal, mp. 85-87° C. MS(CI) 387(M+1). H¹ -NMR (CDCl₃), 3.446 (br.s.,3H, CH3), 5.459 (d, J=7.2Hz, 2H, H₁,4).

d) Preparation of7-carbomethoxy-5-(2-fluoro-5-pyridyl)-7-azabicyclo[2.2.1]hept-2-ene (57)

Use of the method set forth in Example 30 gave compound 57 as a 1:2.5mixture of exo and endo isomers in a total yield of 64% from compound56. MS(CI) 249(M+1). H¹ -NMR (CDCl₃), (for endo-isomer). 3.682 (s, 3H,OCH₃), (for exo-isomer), 3.655 (s, 3H, OCH₃).

e) Preparation of7-carbomethoxy-2-(2-fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (58)

Use of the method set forth in Example 31 gave compound 58 as acolorless oil in a yield of 93.3% from compound 57. MS(CI) 251(M+1). H¹-NMR (CDCl₃), (for endo-isomer), δ 3.722 (s, OCH₃), (for exo-isomer) δ3.671 (s, 3H, OCH₃).

f. Preparation of 2-(2-fluoro-5-pyridyl)-7-azanorbornane (53)

The method set forth in Example 32 was used to produce 23 mg (16.2%) ofthe exo-isomer of compound 53 and 54.8 mg (38%) of the endo isomer ofcompound 53, as an oil from 185 mg of Compound 58 (0.74 mmol). MS(CI)193(M+1). ¹ H-NMR (CDCl₃). δ 2.763 (dd, J=0.8, 9.0Hz, 1H, H₂), 3.532 (s,1H, H1), 3.769 (t, J=3.6Hz, 1H, H₄). (For endo-isomer). δ 3.324 (dt,J=12Hz, 5.7Hz, 1H, H₂), 3.779 (q, J=5.1Hz, 2H, H₁,4).

EXAMPLE 55 Preparation of 2-(2-chloro-3-pyridyl)-7-azanorbornane (59)##STR24## a) Preparation of 1-(2-chloro-3-pyridyl)-2-phenylsulfonylethanone (60)

Use of the method set forth in Example 26 gave compound 60 in 74% yieldfrom 2-chloronicotinyl chloride as white solid, mp. 103-104° C. MS(CI)296, 297(M+1). H¹ -NMR (CDCl₃) δ 4.871 (s, 2H, --CH₂ --).

b) Preparation of 1-(2-chloro-3-pyridyl)-2-phenylsulfonyl acetylene (61)

Use of the method set forth in Example 27 gave compound 61 in 27% yieldfrom compound 60 as a white solid, mp. 90-94° C. MS(CI) 278, 280(M+1).

c) Preparation of7-carbomethoxy-2-(2-chloro-3-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hepta-2,5-diene(62)

Use of the method set forth in Example 29 gave compound 62 in 62.4% from61 as an oil. MS(CI) 403, 405(M+1). H¹ -NMR (CDCl₃), δ 3.612 (s, 3H,OCH₃). 5.429 (t, J=2.1Hz, 1H), 5.497 (t, J=2.1Hz, 1H).

d) Preparation of7-carbomethoxy-5-(2-chloro-3-pyridyl)-7-azabicyclo[2.2.1]hept-2-ene (63)

Use of the method set forth in Example 30, gave compound 63 as theexo-isomer, 12%, and the endo-isomer, 35%. MS(CI) 265, 267(M+1). H¹ -NMR(CDCl₃) (for exo-isomer). δ 3.66 (s, 3H, OCH₃), 6.502 (br.s. 2H, H₅,6).H¹ -NMR (CDCl₃) (for endo-isomer). δ 3.686 (s, 3H, OCH₃), 4.882, 5.029(2br.s. 2H, H₁,4). 5.88, 6.544 (2br.s., 2H, H₅,6).

e) Preparation of7-carbomethoxy-2-(2-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane (64)

Using the method set forth in Example 31, the exo-compound 63 washydrogenated to give compound 64 in quantitative yield. MS(CI) 267,269(M+1). H¹ -NMR (DCCl₃) δ 3.277 (dd, J=4.5, 8.4Hz, 1H, H₂). 3.654 (s,3H, OCH₃).

f) Preparation of 2-(2-chloro-3-pyridyl)-7-azanorbornane (59)

Use of the method set forth in Example 32, gave compound 59 fromexo-compound 64, in 41% yield as an oil. MS(CI) 209, 211(M+1). H¹ -NMR(CDCl₃) δ 3.162 (dd, J=4.8, 8.7Hz, 1H, H₂), 3.681 (s, 1H), 3.795 (t,J=3.6Hz, 1H) (H₁, H₄).

EXAMPLE 56 Preparation of2-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]heptane (65) ##STR25## a)Preparation of 1-(2-chloro-4-pyridyl)-2-phenylsulfonylethanone (66)

Using the method set forth in Example 26, where 2-chloroisonicotinylchloride (see Anderson et al., J. Med. Chem. 1990, 33(b), 1667) was usedinstead of 6-chloronicotinyl chloride, compound 66 was obtained in 51%yield as a white crystal, mp. 124-125.5° C. (methanol). MS(CI) 296,298(M+1).

b) Preparation of 1-(2-chloro-4-pyridyl)-2-phenylsulfonyl acetylene (67)

Using the method set forth in Example 27, compound 67 was obtained in54% yield from compound 66 as a white crystal, mp. 78-79° C. MS(CI) 278,280 (M+1).

c) Preparation of7-carbomethoxy-2-(2-chloro-4-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hepta-2,5-diene(68)

Using the method set forth in Example 29, compound 68 was obtained fromcompound 67 in 68% yield as a slightly brown oil. MS(CI) 403, 405(M+1).H¹ -NMR (CDCl₃) δ 3.502 (br.s. 3H, OCH₃), 5.420, 5.483 (25, 2H, H₁,4),7.065 (s, 2H, H₅,6).

d) Preparation of7-carbomethoxy-5-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]hept-2-ene (69)

Using the method set forth in Example 30, compound 69 was obtained fromthe desulfonation of compound 68 in 13.6% yield as a 1:2 mixture of exo-and endo-isomers. MS(CI) 265, 267(M+1). ¹ H-NMR (CDCl₃), (forendo-isomer) δ 3.682 (s, 3H, OCH₃), (for exo-isomer). δ 3.665 (s, 3H,OCH₃).

e) Preparation of7-carbomethoxy-2-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]heptane (70)

Using the method set forth in Example 31, compound 70 was obtained fromthe hydrogenation of compound 69 in 95% yield. MS(CI) 267, 269(M+1). ¹H-NMR (CDCl₃) (for endo-isomer), δ 3.694 (s, 3H, OCH₃), (forexo-isomer). δ 3.655 (s, 3H, OCH₃).

f) Preparation of 2-(2-chloro-4-pyridyl)-7-azabicyclo[2.2.1]heptane (65)

Using the method set forth in Example 32, compound 65 was obtained fromthe deprotection of compound 70 in 23.6% (exo-isomer). MS(CI) 209,211(M+1). ¹ H-NMR (CDCl₃), δ 2.738 (dd, J=9.0, 5.1Hz, 1H, H₂), 3.629 (d,J=2.4Hz, 1H), 3.791 (br.s., 1H). Some endo-isomer can be isolated.

EXAMPLE 57 Preparation of disodium 7-epibatidinylphosphate (71)##STR26##

Epibatidine (40.0 mg) was dissolved in 3 ml phosphorous oxychloride andthe mixture was refluxed for 3 hours in the absence of moisture. Theexcess reagent was removed in vacuo to give 100 mg 7-epibatidinylphosphoryl dichloride as a brown oily residue. To 28 mg of this residuein 2 ml tetrahydrofuran was added 2 ml 1M sodium hydroxide in ice bath.The mixture was stirred at room temperature for another 4 hours. Afterevaporation of the organic solvent, the aqueous solution was washed withethyl ether (2×5 ml). The aqueous layer was then evaporated in vacuo toca. 0.5 ml and left to stand at room temperature for several hours togive compound 71 as a white crystal. Yield 14 mg (80%). ¹ H-NMR(D₂ O) δ2.745 (p, J=4.5Hz, 1H, H2), 3.723 (br.s., 1H), 3.920 (br.s., 1H). 7.357(d, J=8.4Hz, 1H). 8.073 (dd, J=2.4, 8.4Hz, 1H), 8.263 (d, J=2.4Hz, 1H).³¹ P-NMR (D₂ O). 5.332. Chlorosulfonic acid or other N-sulfate reagentscan be used in place of phosphorus oxychloride, under these reactionconditions to prepare the N-sulfate derivative of epibatidine andanalogs thereto.

EXAMPLE 58 Preparation of 2,3-dehydroepibatidine (72)

Scheme 7 shows the production of compound 72. ##STR27##

a) Preparation of7-carbo-t-butoxy-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hepta-2,5-diene(73)

Using the method set forth in Example 29, compound 73 was obtained fromthe Diels-Alder reaction of1-(2-chloro-5-pyridyl)-2-phenylsulfonylacetylene 22 withN-carbo-t-butoxy pyrrole (N-t-Boc-pyrrole) in 64% yield as a whitesolid. mp. 133-134° C. MS(CI) 445, 447(M+1).

b) Preparation of7-t-boc-2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2-ene(73)

Adduct 73 (445 mg) was dissolved in a mixture of 20 ml methanol and 10ml tetrahydrofuran containing 8 mg platinum oxide. After hydrogenationunder 1 atm hydrogen for 3 hours, the catalyst was removed byfiltration. The filtrate was concentrated in vacuo to give 440 mgresidue. It was solidified after trituration in methanol. Yield 98%. MS(CI) 447, 449 (M+1). H¹ -NMR (CDCl3) δ 1.266 (s, 9H, C(CH₃)₃), 4.905,4.945 (2br.s., 2H, H2,4).

c) Preparation of2-(2-chloro-5-pyridyl)-3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2-ene(75)

Using the method set forth in Example 53e, the t-Boc of compound 74 waseasily deprotected by trifluoro acetic acid at 0° C. to give compound 75in 95.4% yield as a white solid. MS(CI) 347, 349 (M+1). H¹ -NMR (CDCl₃)δ 4.423 (d, J=4.2Hz, 1H), 4.500 (d, J=3.6Hz, 1H) (H₁,4).

d) Preparation of 2,3-dehydroepibatidine (72)

Compound 75 (365 mg) was desulfonated using the method set forth inexample 30 to give 23 mg of compound 72 as a colorless oil. Yield 19%.MS(CI) 207, 209(M+1). H¹ -NMR (CDCl₃) δ 4.323 (s, 1H, H₁), 4.574 (d,J=3.0Hz, 1H, H₄), 6.560 (d, J=2.4Hz, 1H, H₃).

EXAMPLE 59 Preparation of Chloroethylepibatidine (76) ##STR28##

Using the method set forth in Example 44, epibatidine 19 was alkylatedwith 1-chloro-2-bromoethane to give compound 76 in a 35% yield as aclear oil. MS(CI) 271,273, 275(M+1). H¹ -NMR (CDCl₃). δ 3.225, 3.476(25, 2H, H₁,4), 3.568 (t, J=6.6Hz, 2H).

EXAMPLE 60 Preparation of 2-(2-hydroxy-5-pyridyl)-7-azanorbornane (77)

Compound 53 (8.5 mg, 0.044 mmol) was dissolved in 1 ml tert-butanol. Tothis solution was added 1 ml 2M potassium hydroxide. After reflux for 20hours and evaporation of butanol, the mixture was adjusted with 1Mhydrochloric acid to pH 6-7. Evaporation of solvent in vacuo andpurification of product with silica gel preparative thin layerchromatography developing with 20% 7N ammonia methanol in chloroformgave 4.2 mg compound 77 as an oil. Yield 50%. MS(CI) 191(M+1). ¹ H-NMR(CDCl₃) δ 2.554 (br.s., 1H, H₂), 3.503; 3.743 (2br.s., 2H, H₁,4).

EXAMPLE 61 Preparation of 2-(2-methylthio-5-pyridyl)-7-azanorbornane(78) ##STR29##

Using the method set forth in Example 33, compound 78 was obtained in28% yield from sodium methylmercaptanide in ethanol as a colorless oil.MS(CI) 221, 223(M+1). ¹ H-NMR(CDCl₃) δ 2.542 (s, 3H, SCH3), 2.757 (dd,J=5.1, 8.7Hz, 1H, H₂), 3.546, 3.781 (2br.s., 2H, H₁,4).

EXAMPLE 62 Preparation of 5,6-bis(trifluoromethyl) deschloroepibatidine(79)

Scheme 8 shows the preparation of compound 79. ##STR30##

a) Preparation of7-t-Boc-1,2-bis(trifluoromethyl)-7-azabicyclo[2.2.1]hepta-2,5-diene (80)

Compound 80 was prepared according to the procedure set forth in J.Leroy et al, Synthesis, 1982 313.

b) Preparation of7-t-Boc-2,3-bis(trifluoromethyl)-5-(pyridyl)-7-azabicyclo[2.2.1]hept-2-ene(81)

Compound 80 (165 mg, 0.5 mmol) and 105 mg 3-iodopyridine (0.5 mmol) weredissolved in 1 ml dimethyl formamide containing 9 mg palladium acetate,21 mg triphenyl phosphine, 120 mg piperidine and 60 mg 88% formic acid.The mixture was stirred at 60-70° C. under nitrogen for 1.5 hours and atroom temperature overnight. The solvent was removed in vacuo and theresidue was partitioned between methylene chloride and water. Theorganic layer was separated and the aqueous layer was extracted withmethylene chloride. The combined organic layer was washed with saturatedbrine and dried over magnesium sulfate. After removal of solvent invacuo, the residue (218 mg) was separated in silica gel column elutingwith 20% ethyl acetate in petroleum, to give 48 mg unstable compound 81as a red oil. MS(CI) 409(M+1). Yield 23%. ¹ H-NMR(CDCl₃) δ 1.427 (s, 9H,OC(CH₃)₃), 2.974 (dd, J=4.2, 8.4Hz, 1H, H₂), 4.906, 5.147 (2br.s., 2H,H₁,4).

The 5-(2-chloro-5-pyridyl) analog was obtained by replacing theiodopyridine in the above reaction with 2-chloro-5-iodopyridine.

c) Preparation of2,3-bis(trifluoromethyl)-5-pyridyl-7-azabicyclo[2.2.1]hepta-2-ene (82)

Using the method set forth in Example 53e, compound 81 was easilydeprotected with trifluoroacetic acid to give compound 82 in 90% yield.¹ H-NMR (CDCl₃). δ 2.02 (dd, J=8.4, 2.1Hz, 2H, H₃), 2.88 (dd, J=4.8,8.4Hz, 1H, H₂), 4.36, 4.63 (2br.s., 2H, H₁,4).

The 5-(2-chloro-5-pyridyl) analog was obtained in the manner set forthabove.

d) Preparation of 5,6-bis(trifluoromethyl) deschloroepibatidine (79)

Compound 82 was hydrogenated under high pressure of hydrogen, providingcompound 79.

5,6-bis(trifluoromethyl) epibatidine was obtained in the manner setforth above.

IV. Pharmaceutical Compositions

Humans, equine, canine, bovine and other animals, and in particular,mammals, suffering from pain can be treated by administering to thepatient an effective amount of one or more of the above-identifiedcompounds or a pharmaceutically acceptable derivative or salt thereof ina pharmaceutically acceptable carrier or diluent. The active materialscan be administered by any appropriate route, for example, orally,parenterally, intravenously, intradermally, subcutaneously, ortopically, in liquid, cream, gel or solid form.

As used herein, the term pharmaceutically acceptable salts or complexesrefers to salts or complexes that retain the desired biological activityof the above-identified compounds and exhibit minimal undesiredtoxicological effects. Nonlimiting examples of such salts are (a) acidaddition salts formed with inorganic acids (for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, andthe like), and salts formed with organic acids such as acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid,benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, naphthalenedisulfonic acid, andpolygalacturonic acid; (b) base addition salts formed with metal cationssuch as zinc, calcium, bismuth, barium, magnesium, aluminum, copper,cobalt, nickel, cadmium, sodium, potassium, and the like, or with acation formed from ammonia, N,N-dibenzylethylene-diamine, D-glucosamine,tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and(b); e.g., a zinc tannate salt or the like.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount without causing serious toxic effectsin the patient treated. A preferred dose of the active compound for allof the above-mentioned conditions is in the range from about 0.0001 to20 mg/kg, preferably 0.001 to 2 mg/kg per day, more generally 0.05 toabout 0.5 mg per kilogram body weight of the recipient per day. Atypical topical dosage will range from 0.001% to 0.5% wt/wt in asuitable carrier. The effective dosage range of the pharmaceuticallyacceptable derivatives can be calculated based on the weight of theparent compound to be delivered. If the derivative exhibits activity initself, the effective dosage can be estimated as above using the weightof the derivative, or by other means known to those skilled in the art.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing 0.001 to 1000 mg,preferably 0.01 to 500 mg of active ingredient per unit dosage form. Aoral dosage of 0.1 to 200 mg is usually convenient.

The active ingredient can be administered by the intravenous injectionof a solution or formulation of the active ingredient, optionally insaline, or an aqueous medium or administered as a bolus of the activeingredient.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring. When the dosageunit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, dosageunit forms can contain various other materials which modify the physicalform of the dosage unit, for example, coatings of sugar, shellac, orother enteric agents.

The active compound or pharmaceutically acceptable salt or derivativethereof can be administered as a component of an elixir, suspension,syrup, wafer, chewing gum or the like. A syrup may contain, in additionto the active compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The active compound or pharmaceutically acceptable derivatives or saltsthereof can also be mixed with other active materials that do not impairthe desired action, or with materials that supplement the desiredaction, such as antibiotics, antifungals, antiinflammatories, orantiviral compounds.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic. If administered intravenously, preferredcarriers are physiological saline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation.

V. Analgesic Activity of 7-Azabicyclo[2.2.1]-heptanes and -heptenes

A wide variety of biological assays have been used to evaluate theability of a compound to act as an analgesic. Any of these known assayscan be used to evaluate the analgesic ability of the compounds disclosedherein. The Straub-tail reaction, which is characteristic of opiatealkaloids, has been used as an assay for opiate agonists andantagonists. The assay is described in detail in Br. J. of Pharmacol.1969, 36, 225. Another accepted assay for analgesic activity is the hotplate analgesia assay, described in J. of Pharmacol. Exp. Therap. 1953,107, 385. An assay for the evaluation of the ability of a compound tobind to an opiate receptor is described in Mol. Pharmacol. 1974, 10,868.

In addition to their potent central analgesic effects, some of thesubstituted 7-aza-bicyclo[2.2.1]-heptanes and -heptenes described hereinalso possess varying degrees of peripheral anti-inflammatory andanalgesic effects which are useful for therapeutic applications. Thefollowing assays for the evaluation peripheral anti-inflammatoryactivities are described in Barber, A. and Gottschlich, R., OpioidAgonists nd Antagonists: An Evaluation of Their Peripheral Actions inInflammation, Medicinal Research Review, Vol. 12, No.5, 525-562(September, 1992): paw hyperalgesia in rat that has been induced byprostaglandin E2 or carrageenan; inflamed knee joint in cat that hasbeen induced by carrageenan, bradykinin or PGE₂ ; formalin test in mouseor rat that has been induced by formalin; neurogenic inflammation inrat, cat or guinea pig that has been induced by antidromic stimulationof sensory nerves; and the writhing test in mouse that is induced byacetic acid, phenylbenzoquinone, prostaglandin or bradykinin; andadjuvant arthritis in rat that is induced by Freund's adjuvant.

EXAMPLE 63 Evaluation of Analgesic Activity

Table 4 provides the analgesic activity measured as ED₅₀ (μg/Kg) forselected compounds disclosed herein, as determined using the Straub-Tailassay, as describe by J. Daly et al. J. Am. Chem. Soc., 1980, 102, 830;T. F. Spande, et al. J. Am. Chem. Soc. 1992, 114, 3475; T. Li, et al.Bioorganic and Medicinal Chemistry Letters 1993, 3, 2759.

                                            TABLE 4                           

    __________________________________________________________________________    Structural formula  ED.sub.50 μg/Kg                                                                    Comments                                          __________________________________________________________________________                                  9 (R31##                                                                    μg/Kg)              7.5  l-epibatidine                                           d-epibatidine                                  -                                                                                                        >100 2##                                           -                                                                                                        <10 33##                                           -                                                                                                        10000 Mixture of endo  and exo isomers                                      (1.3:1)                                              -                                                                                                        750 35##                                           -                                                                                                        100% @  1000 (μg/Kg)                            -                                                                                                        <1000 ##                                           -                                                                                                        250 38##                                           -                                                                                                        <1000 ##                                           -                                                                                                        100˜200                                      -                                                                                                        ca. 50 #                                           -                                                                                                        ca. 100                                            -                                                                                                        ca. 10 #                                           -                                                                                                        10 racemic                                         -                                                                                                        99% @ 100                                          -                                                                                                        ca. 1000                                        __________________________________________________________________________

EXAMPLE 64 Evaluation of Nicotinic Receptor Binding Activity

7-aza-bicyclo[2.2.1]-heptanes and -heptenes were evaluated for theirability to bind to the acetylcholine nicotinic receptor using a standardbinding assay, e.g. X. Zhang and A. Nordberg, Arch. Pharmacol., 348, 28(1993); R. E. Middleton and J. B. Cohen, Biochemistry, 30, 6987 (1991),with nicotine sulfate as the reference compound, rat cortex as thetissue substrate, and a [³ H]-NMCI radioligand. The results are providedin table 5.

                  TABLE 5                                                         ______________________________________                                        Structural            Testing                                                   Formula Level Inhibition %                                                  ______________________________________                                                                             10TR47##                                                                    .sup.-7 M  10.sup.-9  10.sup.-11 106                                          72   13                                       -                                                                                                               10.sup.-7  10.sup.-9  10.sup.-11                                               10.sup.-7  10.sup.-9  10.sup.-11                                           102   77   10        102   22   5                                               -                                                                             10.sup.-5  10.sup.-7  10.sup.-9 104                                         103  103                                      -                                                                                                               10.sup.-5 M  10.sup.-7  10.sup.-9                                           104  100   49                                 -                                                                                                               10.sup.-7  10.sup.-9  10.sup.-11 104                                          49   22                                     -                                                                                                               10.sup.-7 M  10.sup.-8  10.sup.-9                                           103.9   71.3  5                               -                                                                                                               R = H  R = CH.sub.3 10.sup.-5 M                                             10.sup.-7  10.sup.-5 103   24              ______________________________________                                                                           81                                     

Modifications and variations of the present invention will be obvious tothose skilled in the art from the foregoing detailed description of theinvention. Such modifications and variations are intended to come withinthe scope of the appended claims.

We claim:
 1. An -azabicyclo(2.2.1)-heptane or -heptene compound of theformula: ##STR54## wherein: R¹ and R⁴ are independently hydrogen oralkyl;R³, R⁵ and R⁶ are independently hydrogen, alkyl, alkylhydroxy,alkyloxyalkyl, alkylthioalkyl, alkylamino, alkylaminoalkyl oralkylaminodialkyl, oxyalkyl, thioalkyl, halo, haloalkyl, NH₂, alkylaminoor dialkylamino, cyclic dialkylamino, ##STR55## amidine, ##STR56## --CO₂H; CO₂ alkyl, --C(O)alkyl, --CN, --C(O)NH₂, --C(O)NH(alkyl),--C(O)N(alkyl)₂, allyl, --SO₂ (alkyl), --SO₂ aryl, --S(O)alkyl,--S(O)aryl, aryl; or ##STR57## or pyridyl unsubstituted or substitutedwith halo, oxyalkyl, or CO₂ alkyl, R₅ and R₆ together are optionallyalkylidene or haloalkylidene, epoxide (--O--), episulfide (--S--); imino(--N(alkyl)-- or --N(H)--; R₂ is Q; R⁷ is --CH₂ CH₂ (C₆ H₅),alkylamino(alkyl)₂, alkyloxyalkyl, alkylthioalkyl, dialkyl to from aquaternary ammonium; ##STR58## wherein R⁹ is hydrogen or alkyl; whereinY' is CN, NO₂, alkyl, OH, --O-alkyl; wherein Z is O or S; wherein R¹⁰and R¹¹ are each independently --O, --OH, --O-alkyl, --O-aryl, --NH₂,--NH(akyl), --N(alkyl)₂, --NH(aryl) and --N(aryl)₂ ; wherein Q is##STR59## and wherein the Q moiety is optionally substituted with 1 to 3W substituents; and W is alkyl, halo, aryl, OH, oxyalkyl, SH, thioalkyl,--SO(alkyl), --SO₂ alkyl, OCH₂ CH═CH₂, --OCH₂ (C₆ H₅), CF₃, CN,alkylenedioxy, --CO₂ H, --CO₂ alkyl, --OCH₂ CH₂ OH, --NO₂, --NH₂,--NH(alkyl), --N(alkyl)₂, NHC(O)alkyl, --SO₂ CF₃, or --NHCH₂ aryl, andwherein the - - - indicates an optional double bond.
 2. The compound ofclaim 1, wherein R⁷ is selected from the group consisting of phenethyl,methoxyethyl, methylthioethyl, dimethylaminopropyl and(4-methoxybenzyl).
 3. The compound of claim 1 selected from the groupconsisting of 2-exo-(3-pyridyl) 7-azabicyclo[2.2.1]-heptane;2-endo-(3-pyridyl) 7-azabicyclo[2.2.1]-heptane;7-methyl-2-exo-(3-pyridyl) 7-azabicyclo[2.2.1]-heptane;7-cyclopropylmethyl-2-exo-(3-pyridyl) 7-azabicyclo[2.2.1]-heptane;2-exo-(6-chloro-3-pyridyl) 7-azabicyclo[2.2.1]-heptane;2-exo-(6-fluoro-3-pyridyl) 7-azabicyclo[2.2.1]-heptane and7-phenethyl-2-exo-(3-pyridyl) 7-azabicyclo[2.2.1]-heptane.
 4. Thecompound of claim 1 selected from the group consisting of2-exo-(4-pyridyl) 7-azabicyclo[2.2.1]-heptane;7-methyl-2-exo-(4-pyridyl) 7-azabicyclo[2.2.1]-heptane;7-allyl-2-exo-(4-pyridyl) 7-azabicyclo[2.2.1]-heptane; and7-cyclopropylmethyl-2-exo-(4-pyridyl) 7-azabicyclo[2.2.1]-heptane. 5.The compound of claim 1 selected from the group consisting of2-exo-(3-chloro-4-pyridyl) 7-azabicyclo[2.2.1]-heptane;7-cyclopropylmethyl-2-2-exo-(3-chloro-4-pyridyl)7-azabicyclo[2.2.1]-heptane; and 7-phenethyl-2-exo-(3-chloro-4-pyridyl)7-azabicyclo[2.2.1]-heptane.
 6. The compound of claim 1 selected fromthe group consisting of: 2-exo-(2-fluoro-5-pyridyl)7-azabicyclo[2.2.1]-heptane; 2-exo-(2-methoxy-5-pyridyl)7-azabicyclo[2.2.1]-heptane; 2-exo-(2-methylthio-5-pyridyl)7-azabicyclo[2.2.1]-heptane; 2-exo-(2-methyl-5-pyridyl)7-azabicyclo[2.2.1]-heptane; 2-exo-(2-dimethylamino-5-pyridyl)7-azabicyclo[2.2.1]-heptane, and the 7-cyclopropylmethyl derivatives ofthese compounds.
 7. The compound of claim 1, wherein R¹ and R⁴, areindependently selected from the group consisting of methyl.
 8. Thecompound of claim 1, wherein R³ is selected from the group consisting ofmethyl, hydroxymethyl, methoxymethyl, carboxy, carbamyl, cyano,aminomethyl, dimethylaminomethyl, methylthiomethyl, phenylsulfonyl,methanesulfonyl, benzyl, and allyl.
 9. The compound of claim 1, whereinR⁵ and R⁶ are selected from the group consisting of trifluoromethyl,methoxy, methyl; carbomethoxy, hydroxymethyl, methoxymethyl, chloro,hydroxy.
 10. The compound of claim 1 that has a double bond between C²and C³.
 11. The compound of claim 1 that has a double bond between C⁵and C⁶.
 12. The compound of claim 1, wherein:the 2-substituent isselected from the group consisting of 2-exo-(3-pyridyl),2-exo-(6-chloro-3-pyridyl), and 2-exo-(6-fluoro-3-pyridyl); and the 7substituent is selected from the group consisting of ##STR60##
 13. Amethod for the treatment of inflammatory conditions in a mammal,comprising administering an effective amount of an-azabicyclo(2.2.1)-heptane or -heptene compound of the formula:wherein:R¹ and R⁴ are independently hydrogen or alkyl; R³, R⁵ and R⁶ areindependently hydrogen, alkyl, alkylhydroxy, alkyloxyalkyl,alkylthioalkyl, alkylamino, alkylaminoalkyl or alkylaminodialkyl,oxyalkyl, thioalkyl, halo, haloalkyl, NH₂, alkylamino or dialkylamino,cyclic dialkylamino, ##STR61## amidine, ##STR62## --CO₂ H, CO₂ alkyl,--C(O)alkyl, --CN, --C(O)NH₂, --C(O)NH(alkyl), --C(O)N(alkyl)₂, allyl,--SO₂ (alkyl), --SO₂ aryl, --S(O)alkyl, --S(O)aryl, aryl; or ##STR63##or pyridyl unsubstituted or substituted with halo, oxyalkyl, or CO₂alkyl, R₅ and R₆ together are optionally alkylidene or haloalkylidene,epoxide (--O--), episulfide (--S--); imino (--N(alkyl)--) or --N(H)--;R₂ is Q; R⁷ is --CH₂ CH₂ (C₆ H₅), alkylamino(alkyl)₂, alkyloxyalkyl,alkylthioalkyl, dialkyl to from a quaternary ammonium ##STR64## whereinR⁹ is hydrogen or alkyl; wherein Y' is CN, NO₂, alkyl, OH, --O-alky;wherein Z is O or S; wherein R¹⁰ and R¹¹ are each independently --O⁻,--OH, --O-alkyl, --O-aryl, --NH₂, --NH(alkyl), --N(alkyl)₂, --NH(aryl)and --N(aryl)₂, wherein Q is ##STR65## and wherein the Q moiety isoptionally substituted with 1 to 3 W substituents, and W is alkyl, halo,aryl, OH, oxyalkyl, SH, thioalkyl, --SO(alkyl), --SO₂ alkyl, OCH₂CH═CH₂, --OCH₂ (C₆ H₅), CF₃, CN, alkylenedioxy, --CO₂ H, --CO₂ alkyl,--OCH₂ CH₂ OH, --NO₂, --NH₂, --NH(alkyl), --N(alkyl)₂, NHC(O)alkyl,--SO₂ CF₃, or --NHCH₂ aryl, and wherein the - - - indicates an optionaldouble bond.
 14. The method of claim 13, wherein the compound isadministered in an amount ranging between 0.002 and 10 mg/kg per day.15. The method of claim 13, wherein the compound is administered in anamount ranging between 0.02 and 0.2 mg/kg per day.
 16. The method ofclaim 13, wherein the compound is applied topically in a dosage rangingbetween 0.001% and 0.5% wt/wt in a carrier suitable for topicaladministration.
 17. The method of claim 13, wherein the compound isadministered by intravenous injection.
 18. The method of claim 13,wherein the compound is administered orally.
 19. The method of claim 13,wherein the compound is administered topically.
 20. A method forimparting analgesia to a mammal, comprising administering an effectiveamount of an -azabicyclo(2.2.1)-heptane or -heptene compound of theformula: ##STR66## wherein: R¹ and R⁴ re independently hydrogen oralkyl;R³, R⁵ and R⁶ are independently hydrogen, alkyl, alkylhydroxy,alkyloxyalkyl, alkylthioalkyl, alkylamino, alkylaminoalkyl oralkylaminodialkyl, oxyalkyl, thioalkyl, halo, haloalkyl, NH₂, alkylaminoor dialkylamino, cyclic dialkylamino, ##STR67## amidine, ##STR68## --CO₂H; CO₂ alkyl, --C(O)alkyl, --CN, --C(O)NH₂, --C(O)NH(alkyl),--C(O)N(alkyl)₂, allyl, --SO₂ (alkyl), --SO₂ aryl, --S(O)alkyl,--S(O)aryl, aryl; or ##STR69## or pyridyl unsubstituted or substitutedwith halo, oxyalkyl, or CO₂ alkyl, R₅ and R₆ together are optionallyalkylidene or haloalkylidene, epoxide (--O--), episulfide (--S--); imino(--N(alkyl)--) or --N(H)--; R₂ is Q; R⁷ is --CH₂ CH₂ (C₆ H₅),alkylamino(alkyl)₂, alkyloxyalkyl, alkylthioalkyl, quaternary dialkylammonium ##STR70## wherein R⁹ is hydrogen or alkyl; wherein Y' is CN,NO₂, alkyl, OH, --O-alkyl; wherein Z is O or S; wherein R¹⁰ and R¹¹ areeach independently --O⁻, --OH, --O-alkyl, --O-aryl, --NH₂, --NH(alkyl),--N(alkyl)₂, --NH(aryl) and --N(aryl)₂, wherein Q is ##STR71## andwherein the Q moiety is optionally substituted with 1 to 3 Wsubstituents; and W is alkyl, halo, aryl, OH, oxyalkyl, SH, thioalkyl,--SO(alkyl), --SO₂ alkyl, OCH₂ CH═CH₂, --OCH₂ (C₆ H₅), CF₃, CN,alkylenedioxy, --CO₂ H, --CO₂ alkyl, --OCH₂ CH₂ OH, --NO₂, --NH₂,--NH(alkyl), --N(alkyl)₂, NHC(O)alkyl, --SO₂ CF₃, or --NHCH₂ aryl, andwherein the - - - indicates an optional double bond.
 21. The method ofclaim 20, wherein the compound is administered in an amount rangingbetween 0.002 and 10 mg/kg per day.
 22. The method of claim 20, whereinthe compound is administered in an amount ranging between 0.02 and 0.2mg/kg per day.
 23. The method of claim 20, wherein the compound isapplied topically in a dosage ranging between 0.001% and 0.5% wt/wt in acarrier suitable for topical administration.
 24. The method of claim 20,wherein the compound is administered by intravenous injection.
 25. Themethod of claim 20, wherein the compound is administered orally.
 26. Themethod of claim 20, wherein the compound is administered topically. 27.A process for the preparation of 7-azabicyclo [2.2.1]-heptanes and-heptenes, comprising the steps of(i) combining a pentaammineosmium (II)complex of an optionally substituted pyrrole and a dipolarophile whereinthe dipolarophile is selected from the group consisting of a halogensubstituted vinyl-pyridine, alkyl acrylate, alkyl methacrylate, pyridylsubstituted vinyl sulfones, acrylonitriles, anhydrides, maleimides,alpha-methylene-δ-butyrolactone, maleate, and fumarate,to form anoptionally substituted 7-azabicyclo[2.2.1]heptene osmium complex; andthen (ii) removing the pentaammineosmium from the7azabicyclo[2.2.1]heptene.
 28. The process of claim 27, wherein thepyrrole is selected from the group consisting of 2,5-dialkylpyrrole,2-alkylpyrrole, 3-alkylpyrrole, 1-alkylpyrrole, 3,4-dialkylpyrrole,pyrrole, 1-silylated pyrrole, (1, 2, or 3)-alkoxy or amino pyrrole,2,3-dialkoxypyrrole, 2,5-dialkoxypyrrole, and 3,4-dialkoxypyrrole. 29.The process of claim 27, wherein the dipolarophile is Z¹ --C═C--Z²,wherein Z¹ and Z² are electron-withdrawing groups.
 30. The process ofclaim 29, wherein Z¹ and Z² are independently selected from the groupconsisting of CO(alkyl, aryl or heteroaryl), C(O)H, CO₂ (alkyl, aryl, orheteroaryl), or SO₂ (alkyl, aryl, or heteroaryl), or wherein Z¹ and Z₂are together (CO)₂ O or (CO)₂ NR⁸, wherein R¹² is alkyl including CH₃ orC₂ H₅ ; aryl including phenyl, or heteroaryl.
 31. The process of claim27, wherein the dipolarophile is selected from the group consisting of ahalogen substituted vinyl-pyridine, alkyl acrylate, alkyl methacrylate,pyridyl substituted vinyl sulfones, acrylonitriles, anhydrides,maleimides, alpha-methylene-δ-butyrolactone, maleate, and fumarate. 32.The process of claim 27, wherein pentaammineosmium(II) is generated insitu by the reduction of pentaammineosmium(III) with a one electronreducing agent that has a reducing potential of less than -0.75 voltsversus hydrogen.
 33. The process of claim 27, wherein the counteranionof the pentaammineosmium is selected from the group consisting of CF₃SO₃ ⁻, PF₆ ⁻, and (alkyl or aryl) SO₃ ⁻.
 34. The process of claim 31,wherein the reducing agent is selected from the group consisting ofmagnesium, zinc, aluminum, sodium, lithium, and cobaltacene.
 35. Theprocess of claim 32, wherein the optionally substituted pyrrole,pentaammineosmium (III), and reducing agent are stirred at a temperatureranging between 0 and 50 degrees C., until the desired organometalliccomplex is formed.
 36. The process of claim 27, further comprisingderivatizing functional groups on the 7-azabicyclo[2.2.1]heptene whilepentaammineosmium is complexed to the pi-orbital of the heptene moiety.37. The process of claim 27, further comprising reducing the optionallysubstituted 7-azabicyclo[2.2.1]heptene to an optionally substituted7-azabicyclo[2.2.1]heptane.
 38. A process for the preparation ofoptionally substituted 7-azabicyclo[2-2.1]-heptanes and -heptenes,comprising the steps of combining a N-(electron withdrawingsubstituted)-optionally substituted pyrrole with anarylsulfonyl(optionally substituted aryl or heterocyclic)acetylene. 39.The process of claim 38, wherein the pyrrole is selected from the groupconsisting of 3,4-di(CF3)pyrrole, 3-(thioalkyl)pyrrole,2,5-dialkylpyrrole, 3,4-bis(trifluoromethyl)pyrrole, 2-alkylpyrrole,2-alkoxyalkylpyrrole, 2-alkylthioalkylpyrrole,2-dialkylaminoalkylpyrrole, alkylpyrrole 2-acetate,2-alkoxyalkoxyalkylpyrrole, 3-aryloxyalkylpyrrole, 2-alkoxypyrrole,3-alkoxypyrrole, 3-aryloxypyrrole, 3,4-dialkylpyrrole, and3-alkylpyrrole.
 40. The process of claim 38, wherein theN-electron-withdrawing group is selected from the group consisting ofcarbomethoxy, carbobenzyloxy, and tert-butoxycarbonyl.
 41. Apharmaceutical composition comprising an effective amount to impartanalgesia to a mammal of the compound of claim 1 or its pharmaceuticallyacceptable salt, in a pharmaceutically acceptable carrier or diluent.42. A pharmaceutical composition comprising an effective amount to treatinflammation in a mammal of the compound of claim 1 or itspharmaceutically acceptable salt, in a pharmaceutically acceptablecarrier or diluent.
 43. The method of claim 13, wherein the mammal is ahuman.
 44. The method of claim 20, wherein the mammal is a human. 45.The pharmaceutical composition of claim 42, wherein the mammal is ahuman.